Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To investigate the effects of fenofibrate on the prevention and progression of diabetic retinopathy.
Background
Description of the condition
Globally, from an overall 32.4 million blind and 191 million visually impaired people, 0.8 million were blind and 3.7 million were visually impaired due to diabetic retinopathy in 2010 (Leasher 2016). Age‐standardised prevalence of diabetic retinopathy‐related blindness or visual impairment was higher in sub‐Saharan Africa and South Asia (Leasher 2016). Extrapolated to the world diabetes population in 2010, one study has estimated that approximately 93 million people may have any diabetic retinopathy, and 28 million people may have sight‐threatening stages of diabetic retinopathy (Yau 2012). In addition to constituting a physical burden to patients, society bears an economic burden because of treating diabetic retinopathy. Several studies in Europe, USA and Asia have recently reported association of higher medical costs with diabetic retinopathy (Heintz 2010; Romero‐Aroca 2016; Schmier 2009; Woung 2010; Zhang 2017). The total healthcare costs of diabetic retinopathy in Sweden is up to approximately EUR 9.9 million per year, and the annual cost for diabetic retinopathy was EUR 106,000 per 100,000 inhabitants when considering a 4.8% prevalence of diabetes (Heintz 2010). A study in Singapore reported that the presence and severity of diabetic retinopathy was associated with increased direct medical costs (Zhang 2017).
Description of the intervention
Diabetic retinopathy is the most common microvascular complication of diabetes, in which high blood sugar leads to damage of the blood vessels in the retina. The cells (endothelial cells and pericytes) in the small retinal blood vessels (capillaries) are lost as a result of diabetes and these 'acellular' capillaries are non‐functioning with a subsequent reduction or cessation of blood supply to the retina. As the blood vessels become weak, fluid contained in them also leaks out, leading to oedema (accumulation of fluid) in the retina. When the fluid accumulates in the centre of the retina, the macula, diabetic macular oedema (DMO) ensues (Tan 2017). The lack of blood supply to the retina is compensated by the retina forming 'new vessels', which are abnormal and fragile; this is known as proliferative diabetic retinopathy (PDR) (Evans 2014).
Strict control of blood glucose levels and blood pressure is essential to reduce the risk of sight loss as a result of the complications of diabetic retinopathy, namely DMO and PDR but is often difficult to achieve. In some people with diabetes, DMO and PDR may still occur even if glucose levels and blood pressure are well controlled. Laser photocoagulation, intravitreous injections of anti‐vascular endothelial growth factor (VEGF) agents and corticosteroids are used to treat DMO and PDR (Duh 2017; Evans 2014; Gross 2015; McCulloch 2017). Therapeutic strategies to prevent the development of the end‐stage complications of diabetic retinopathy are, though, lacking and very much needed.
Fenofibrate, a fibrate indicated for mixed dyslipidaemia and hypertriglyceridaemia, came on to the market in 1975, and is widely used in over 90 low‐, middle‐ and high‐income countries. Its cost is quite low, for example, the equivalent of INR 90 a day in India. The main clinical effects are mediated by peroxisome proliferator‐activated receptor (PPAR) alpha activation and consist of a moderate reduction in total cholesterol and low‐density lipoprotein cholesterol (LDL‐C) levels, a marked reduction in triglycerides (TG) and an increase in high‐density lipoprotein cholesterol (HDL‐C).
How the intervention might work
Fenofibrate is a peroxisome proliferator‐activated receptor alpha agonist (PPAR‐alpha). PPAR‐alpha is highly expressed in tissues with high mitochondrial and peroxisomal fatty‐acid beta‐oxidation rates, such as the retina (Ciudin 2013). It has been reported that PPAR‐alpha is downregulated in the retinas of both type 1 and type 2 diabetic models and that high glucose is a cause of PPAR‐alpha downregulation (Hu 2013). PPAR‐ alpha knockout mice develop vascular leakage, leukostasis, pericyte loss, capillary degeneration and overexpression of inflammatory markers (Hu 2013), all features observed in diabetic retinopathy in humans. Therefore, fenofibrate may help reverse the effects of diabetes in the retina. Other reported mechanisms through which fenofibrate may ameliorate diabetic retinopathy include modulating Nrf2 signalling and NLRP3 inflammasome activation, and by cytochrome P450 Epoxygenase (CYP)2C inhibition (Gong 2016; Liu 2017).
Why it is important to do this review
The number of people with diabetes as well as the number of people suffering from diabetic retinopathy is increasing worldwide. As described above, laser photocoagulation, anti‐VEGFs and steroids are only used for the treatment of established DMO and PDR (Aiello 2010; Boyer 2014; Gross 2015; Sivaprasad 2017; Virgili 2017), but not to prevent their occurrence nor to prevent the development and progression of diabetic retinopathy. Fenofibrate may be useful for this purpose.
Objectives
To investigate the effects of fenofibrate on the prevention and progression of diabetic retinopathy.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) only.
Types of participants
Participants will be people diagnosed with type 1 or 2 diabetes. We will include those who do not have retinopathy or who had diabetic retinopathy at baseline.
Types of interventions
Intervention: fenofibrate (any dose/regimen)
Comparison: placebo or observation
Types of outcome measures
Studies will not be excluded if no outcome data are available, unless it is clear that none of the following outcomes were measured.
Primary outcomes
Progression of diabetic retinopathy
'Progression' is defined as moving from no previously overt retinopathy to any overt retinopathy; or, for people with any overt retinopathy already present, advancing two or more steps in the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale, based on evaluation of stereoscopic or non‐stereoscopic colour fundus photographs of participants who had diabetic retinopathy at baseline (ETDRS Research Group 1991).
Secondary outcomes
Incidence of overt retinopathy
Mean change in visual acuity
Proportion of participants with a reduction in visual acuity of 10 ETDRS letters or more
Incidence of PDR
Incidence of DMO
Additional treatments for diabetic retinopathy (focal/grid laser, panretinal photocoagulation, anti‐VEGFs, steroids, vitrectomy, other)
Mean vision‐related quality of life
Incremental cost per Quality Adjusted Life years (QALY) gained
Acceptability of the treatment
Proportion of participants in which treatment is discontinued
All outcomes will be considered at one, three and five years (plus or minus six months for each time point).
Adverse effects
Rhabdomyolysis, hepatic disorder, pancreatitis, Stevens‐Johnson Syndrome and any others that are reported. We will use the original study authors' definitions for serious adverse events.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist will search the following electronic databases for randomised controlled trials and controlled clinical trials. There will be no restrictions on language or year of publication.
Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 1).
MEDLINE Ovid (1946 to present) (Appendix 2).
Embase Ovid (1980 to present) (Appendix 3).
ISRCTN registry (www.isrctn.com/editAdvancedSearch) (Appendix 4).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 5).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 6).
Searching other resources
We (KI, SYK, SK) will search the reference lists of identified clinical trials. We will perform an additional handsearch for proceedings of scientific meetings focusing on retinopathy, ophthalmology and diabetes.
We will handsearch the European Association for the Study of Diabetes (EASD) congress and the European Association for the Study of Diabetes Eye Complications Study Group (EASDEC) congress from 1990 to the present.
Data collection and analysis
We will conduct trial selection, data extraction and management using Covidence.
Selection of studies
Three review authors (KI, SYK, SK) will independently screen the search results and select trials for inclusion. We will resolve disagreements through discussion. We will screen the list of citations and abstracts and classify records into 'possibly relevant' and 'definitely not relevant'. For the records we identify as 'possibly relevant' we will obtain the full‐text articles. Following the Criteria for considering studies for this review section, we will classify trials into 'to be included' or 'to be excluded'. We will give the primary reasons for exclusion in the Excluded studies table.
Data extraction and management
Two review authors (KI, SK) will independently extract data from trial reports and enter the data into Review Manager 5 (RevMan 5) (Review Manager 2014). Where information available from the full‐text articles is insufficient, we will contact the original trial authors to request additional information. We will resolve any differences in opinion through discussion. If we cannot reach consensus, we will consult a third review author (SYK). We will use a data collection form (Appendix 7), and plan to pilot the form. We will obtain English translations of any trial reported in a language other than English before extracting data. We will obtain the following data on outcomes specified in Types of outcome measures: for dichotomous outcomes, we will collect data on the number of events and total participants randomised as well as followed up in each trial arm; for continuous outcomes, we will collect data on the mean and standard deviation in each trial arm.
Assessment of risk of bias in included studies
Three review authors (KI, SYK, SK) will independently assess study quality, study limitations and the extent of potential bias by using the Cochrane ’Risk of bias’ tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We will consider the following domains.
Sequence generation (selection bias)
Allocation concealment (selection bias)
Masking (blinding) of participants, personnel and outcomes assessors (performance and detection bias)
Incomplete outcome data (attrition bias)
Selective outcome reporting (reporting bias)
Other ‐ other threats to validity
For each domain, we will judge whether the trial authors have made sufficient attempts to minimise bias in their study design. We will make judgements using three measures: high, low and unclear risk of bias. We will record this judgement in the ‘Risk of bias’ tables and will present a summary ‘Risk of bias’ figure.
Measures of treatment effect
We will measure treatment effect according to the data types described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).
Dichotomous data
Variables in this group include the primary outcome, progression of diabetic retinopathy. Variables in this group also include the secondary outcomes, incidence of overt retinopathy, proportion of participants with a reduction in visual acuity of 10 ETDRS letters or more, incidence of PDR, incidence of DMO, acceptability of the treatment and proportion of participants in which treatment is discontinued. We will report dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs).
Continuous data
We will report continuous variables including difference between groups on mean change of visual acuity, quality‐of‐life scores, incremental cost per QALY gained as mean difference with 95% CI (if normally distributed) or median and interquartile range (if not normally distributed). We will calculate the standardised mean difference (SMD) when trials use different scales for the same outcome assessment.
Unit of analysis issues
We anticipate that studies will be individually randomised trials where people are allocated to fenofibrate or control.
Trials reporting one eye per person
There is no unit of analysis issue. We will document how the trials selected the eye to be included in the study. .
Trials reporting two eyes per person
Ideally such studies will adjust for within‐person correlation. If so, we will collect data on the measure of effect and confidence interval and enter this into RevMan 5 using the generic inverse variance method (Review Manager 2014). If trials reported both eyes without this adjustment, we will use these data and discuss the implications of this in the interpretation.
Dealing with missing data
When there are missing data, we will contact the authors of the primary trials to obtain the missing data and the reason why the data are missing. If it is not possible to obtain the missing data, we will explain why we could not get them. We will document when loss to follow‐up was high (over 20%), or unbalanced between treatment groups, as a potential source of attrition bias. We will use data as reported in the trial reports, including any imputation for missing data.
Assessment of heterogeneity
We will assess heterogeneity between trials by visual inspection of forest plots, and by formal statistical tests of heterogeneity (Chi² test (Deeks 2017)). If there is evidence of substantial heterogeneity (defined as I² statistic greater than 50% (Higgins 2003)), and sufficient numbers of trials are available (i.e. 10), we will explore the possible reasons for heterogeneity using subgroup and sensitivity analyses.
Assessment of reporting biases
We will search both registered trials and published trials, and we will report the proportion of unpublished trials among registered trials. We will contact researchers of the unpublished trials to provide data related to outcomes in this review. If we cannot obtain the data, we will describe them in the review. If we include 10 studies or more in the meta‐analysis, we will create a funnel plot and interpret asymmetry as indicating possible publication bias (Sterne 2017).
Data synthesis
We plan to perform statistical analyses according to guidance from Cochrane Eyes and Vision. We will pool data using a random‐effects model, unless there are three or fewer trials, in which case we will use a fixed‐effect model. In case of substantial clinical or statistical heterogeneity, we will not combine study results but present a narrative or tabulated summary.
Subgroup analysis and investigation of heterogeneity
If a sufficient number of studies is available, we will perform the following subgroup analyses to investigate whether the presence or absence of particular covariates explains the variability in effect sizes.
Type of diabetes (type 1 or type 2)
Age groups (65 years or younger, or older than 65 years)
With or without dyslipidaemia at baseline (TG 150 mg/dL or more than 150mg/dl, or less than 150 mg/dL)
With or without overt retinopathy at baseline (the ETDRS Final Retinopathy Severity Scale for Persons of step 3 or less, or step 4 or greater)
Local treatments used (laser photocoagulation and/or anti‐VEGFs and/or intravitreal steroids)
The severity of diabetes (HbA1c 7.0% or more than 7.0%, or less than 7.0%)
Sensitivity analysis
We plan to perform sensitivity analyses for the following factors if applicable.
We will include only studies of adequate methodology (low risk of bias), defined as adequate randomisation and allocation concealment, using proper methods for dealing with incomplete outcome data and masking of intervention and measurement.
We will exclude industry‐funded studies and see whether it makes a difference to the effect estimate.
Summary of findings
We will report absolute risks and measures of effect in a 'Summary of findings' table, providing an overall assessment of the certainty of the evidence for each outcome using the GRADE system (GRADEpro GDT 2015). Three review authors (KI, SYK, SK) will independently perform the GRADE assessment.
We plan to include the following outcomes in the 'Summary of findings' tables. We will report these outcomes at three years.
Progression of retinopathy
Incidence of overt retinopathy
Proportion of participants with visual acuity loss of 10 ETDRS letters or more
Incidence of PDR
Incidence of DMO
Vision‐related quality of life
Adverse effects
Acknowledgements
Cochrane Eyes and Vision (CEV) will create and execute the electronic search strategies. We thank Emily Chew and Jennifer Evans for their comments on this protocol and Anupa Shah for her assistance throughout the editorial process.
Appendices
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Diabetic Retinopathy] explode all trees #2 (diabet* or proliferative or non‐proliferative) near/4 retinopath* #3 diabet* near/3 (eye* or vision or visual* or sight*) #4 retinopath* near/3 (eye* or vision or visual* or sight*) #5 DR near/3 (eye* or vision or visual* or sight*) #6 #1 or #2 or #3 or #4 or #5 #7 MeSH descriptor: [Fenofibrate] this term only #8 fenofibrate or phenofibrate #9 antara or controlip or durafenat or fenoglide or fenobeta or fenofanton or lipofen or lipanthyl or lipantil or liparison or livesan or lofibra or normalip or procetofen or procetofene or secalip or supralip or tricor or triglide #10 #7 or #8 or #9 #11 #6 and #10
Appendix 2. MEDLINE Ovid search strategy
1. randomized controlled trial.pt. 2. random$.ab,ti. 3. placebo.ab,ti. 4. dt.fs. 5. trial.ab,ti. 6. (group or groups).ab,ti. 7. or/1‐6 8. exp animals/ 9. exp humans/ 10. 8 not (8 and 9) 11. 7 not 10 12. exp Diabetic Retinopathy/ 13. ((diabet$ or proliferative or non‐proliferative) adj4 retinopath$).tw. 14. diabetic retinopathy.kw. 15. (diabet$ adj3 (eye$ or vision or visual$ or sight$)).tw. 16. (retinopath$ adj3 (eye$ or vision or visual$ or sight$)).tw. 17. (DR adj3 (eye$ or vision or visual$ or sight$)).tw. 18. or/12‐17 19. Fenofibrate/ 20. (fenofibrate or phenofibrate).tw. 21. (antara or controlip or durafenat or fenoglide or fenobeta or fenofanton or lipofen or lipanthyl or lipantil or liparison or livesan or lofibra or normalip or procetofen or procetofene or secalip or supralip or tricor or triglide).tw. 22. or/19‐21 23. 18 and 22 24. 11 and 23
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.
Appendix 3. Embase Ovid search strategy
1. exp randomized controlled trial/ 2. exp randomization/ 3. exp double blind procedure/ 4. exp single blind procedure/ 5. random$.tw. 6. or/1‐5 7. (animal or animal experiment).sh. 8. human.sh. 9. 7 and 8 10. 7 not 9 11. 6 not 10 12. exp clinical trial/ 13. (clin$ adj3 trial$).tw. 14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. 15. exp placebo/ 16. placebo$.tw. 17. random$.tw. 18. exp experimental design/ 19. exp crossover procedure/ 20. exp control group/ 21. exp latin square design/ 22. or/12‐21 23. 22 not 10 24. 23 not 11 25. exp comparative study/ 26. exp evaluation/ 27. exp prospective study/ 28. (control$ or prospectiv$ or volunteer$).tw. 29. or/25‐28 30. 29 not 10 31. 30 not (11 or 23) 32. 11 or 24 or 31 33. exp Diabetic Retinopathy/ 34. ((diabet$ or proliferative or non‐proliferative) adj4 retinopath$).tw. 35. diabetic retinopathy.kw. 36. (diabet$ adj3 (eye$ or vision or visual$ or sight$)).tw. 37. (retinopath$ adj3 (eye$ or vision or visual$ or sight$)).tw. 38. (DR adj3 (eye$ or vision or visual$ or sight$)).tw. 39. or/33‐38 40. Fenofibrate/ 41. (fenofibrate or phenofibrate).tw. 42. (antara or controlip or durafenat or fenoglide or fenobeta or fenofanton or lipofen or lipanthyl or lipantil or liparison or livesan or lofibra or normalip or procetofen or procetofene or secalip or supralip or tricor or triglide).tw. 43. or/40‐42 44. 39 and 43 45. 32 and 44
Appendix 4. ISRCTN search strategy
(fenofibrate OR phenofibrate OR tricor) AND diabetic retinopathy
Appendix 5. ClinicalTrials.gov search strategy
(fenofibrate OR phenofibrate OR tricor) AND (diabetic retinopathy)
Appendix 6. WHO ICTRP search strategy
diabetic retinopathy = Condition AND fenofibrate OR phenofibrate OR tricor = Intervention
Appendix 7. Data on study characteristics
| Mandatory items | Optional items | |
| Methods | ||
| Study design |
Exclusions after randomisation Losses to follow‐up Number randomised/analysed How were missing data handled? e.g., available case analysis, imputation methods Reported power calculation (Y/N), if yes, sample size and power Unusual study design/issues |
|
| Eyes or Unit of randomisation/ unit of analysis |
Two eyes included in study, both eyes received same treatment, briefly specify how analysed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) and specify if mixture one eye and two eye | |
| Participants | ||
| Country | Setting Ethnic group Equivalence of baseline characteristics (Y/N) |
|
| Total number of participants | This information should be collected for total study population recruited into the study. If these data are only reported for the people who were followed up only, please indicate. | |
| Number (%) of men and women | ||
| Average age and age range | ||
| Inclusion criteria | ||
| Exclusion criteria | ||
| Interventions | ||
| Intervention (n= ) Comparator (n= ) |
|
|
| Outcomes | ||
| Primary and secondary outcomes as defined in study reports | List outcomes Adverse events reported (Y/N) Length of follow‐up and intervals at which outcomes assessed |
Planned/actual length of follow‐up |
| Notes | ||
| Date conducted | Specify dates of recruitment of participants mm/yr to mm/yr | Full study name: (if applicable) Reported subgroup analyses (Y/N) Were trial investigators contacted? |
| Sources of funding | ||
| Declaration of interest | ||
Contributions of authors
KI produced the first draft of the protocol. NL edited subsequent drafts.
SYK, SK, TAF and NW reviewed and commented on subsequent drafts.
Sources of support
Internal sources
No sources of support supplied
External sources
-
National Institute for Health Research (NIHR), UK.
- Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
- This protocol was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base.
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Declarations of interest
KI: none known SYK: none known SK: none known TAF has received lecture fees from Eli Lilly, Janssen, Meiji, MSD, Otsuka, Pfizer and Tanabe‐Mitsubishi, and consultancy fees from Sekisui Chemicals. He has received royalties from Igaku‐Shoin and Nihon Bunka Kagaku‐sha publishers. He has received research support from Mochida and Tanabe‐Mitsubishi. NL: none known NW has research funds from the Japanese Ministry of Health Labor and Welfare and the Japanese Ministry of Education, Science, and Technology. He has also received royalties from Sogensha, Paquet and Akatsuki. The results in the review are completely independent of the intention of these grants.
New
References
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