• Jennifer Perais, Ridhi Agarwal, Jennifer R Evans, Emma Loveman, Jill L Colquitt, David Owens, Ruth E Hogg, John G Lawrenson, Yemisi Takwoingi, and Noemi Lois.
• The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
• Cochrane Db Syst Rev. 2023 Feb 22; 2 (2): CD013775CD013775.

BackgroundDiabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage.  OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR.Search MethodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication.  SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong.  DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.   MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR.  AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

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