Evidence reviews for prognostic factors for progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy and diabetic macular oedema

Cover of Evidence reviews for prognostic factors for progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy and diabetic macular oedema

Evidence reviews for prognostic factors for progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy and diabetic macular oedema

Diabetic retinopathy: management and monitoring

Evidence review A

NICE Guideline, No. 242

London: National Institute for Health and Care Excellence (NICE); 2024 Aug.

ISBN-13: 978-1-4731-6429-1

1. Prognostic factors for the progression of non-proliferative diabetic retinopathy

1.1. Review question

What are the prognostic factors for the progression of non-proliferative diabetic retinopathy in people with diabetic retinopathy to?

proliferative diabetic retinopathy
diabetic macular oedema
diabetic macular ischaemia

1.1.1. Introduction

For people with diabetes, previous research has suggested that poor glycaemic control and hypertension are established risk factors for developing diabetic retinal disease in type I diabetes. This review assessed whether other risk factors can predict the progression from non-proliferative diabetic retinopathy to proliferative diabetic retinopathy, diabetic macular oedema, or diabetic macular ischemia. Many studies have examined the risk factors for developing any sight-threatening retinopathy, but few studies have focused on the risks of developing maculopathy. This review aimed to identify the risk factors associated with the development of diabetic maculopathy or diabetic proliferative disease. Predicting who is most at risk of progression is important to help determine who should receive more frequent monitoring and earlier treatment.

1.1.2. Summary of the protocol

Table 1

Summary of the PICO.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A and the methods document.

A Cochrane review (Perais et al. 2020) was identified which assessed prognostic risk factors for predicting the development of proliferative diabetic retinopathy. Results from this Cochrane review were used for the part of this review which covers risk factors for progression from non-proliferative diabetic retinopathy to proliferative diabetic retinopathy. The review was judged to be high quality and directly applicable to the review (see Appendix D) and so information for this part of the review was taken directly from the Cochrane review, rather than undertaking a new literature search or data analysis (see Table 2 in the methods document). The Cochrane review searched for a wider list of prognostic factors than were included in this review. It also included study types that were not included within the current review protocol, such as case-control studies. Studies that reported on the same outcomes but adjusted for different factors were reported separately, rather than combined into a meta-analysis. Only the 27 studies from the Cochrane review that matched the protocol for this review have been included and reported here.

The section of the review for progression to diabetic macular oedema or macular ischemia originally planned to include only studies consisting of cohorts of patients with non-proliferative diabetic retinopathy at baseline. However, on evaluation of potentially eligible studies and prior to commencing data extraction, it was decided to make a protocol deviation to incorporate those in which a proportion had no retinopathy, or proliferative diabetic retinopathy at baseline. This is because it became apparent that most studies included assorted populations of patients with and without diabetic retinopathy at baseline. The committee agreed that this would be appropriate and so studies with these mixed populations were included in the review and downgraded for applicability.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Prognostic evidence

1.1.4.1. Included studies

A search was carried out to identify studies which evaluated risk factors for progression to diabetic macular oedema and diabetic macular ischemia. 2279 results were identified, of which 54 were identified as potential included studies at abstract level. Full text articles were ordered and reviewed against the inclusion criteria, of which 3 met the inclusion criteria for this review. Three multivariate prospective cohort studies were identified, each of which considered the progression from non-proliferative diabetic retinopathy to diabetic macular oedema. None of the evidence reported prognostic factors for progression to diabetic macular ischemia.

All the studies in the Cochrane review were assessed and 27 matched the prognostic factors and study design in the review.

Prognostic factors for progression to proliferative diabetic retinopathy (some studies reported on more than one prognostic factor):

Evidence from 1 study – socioeconomic status,
Evidence from 2 studies – cholesterol, triglycerides, estimated glomerular filtration rate, diabetic retinopathy features at baseline.
Evidence from 3 studies – ethnicity, diabetic retinopathy severity at baseline
Evidence from 4 studies – gender, duration of diabetes, diastolic blood pressure, systolic blood pressure
Evidence from 5 studies – BMI
Evidence from 6 studies – smoking
Evidence from 13 studies – HbA1C

Prognostic factors for progression to diabetic macular oedema:

Evidence from 1 study – gender, diastolic blood pressure, systolic blood pressure, cholesterol, triglycerides, estimated glomerular filtration rate, hypertension.
Evidence from 2 studies – HbA1C

See Appendix C for the study selection flow chart.

1.1.4.2. Excluded studies

51 studies were excluded following examination of the full text articles.

See Appendix I for excluded studies and reasons for exclusion.

1.1.5. Summary of studies included in the prognostic evidence

Table 2

Prognostic factors for progression to proliferative diabetic retinopathy included from Cochrane review.

Table 3

Included studies of prognostic factors for progression to diabetic macular oedema (NICE review).

See Appendix D for full evidence tables.

1.1.6. Summary of the evidence

People progressing to proliferative diabetic retinopathy

Data from the Cochrane review (Perais et al. 2020)

Table 4

Gender - Studies undertaking multivariable regression analyses to determine the effect of gender on progression to proliferative diabetic retinopathy.

Table 5

Race -Studies undertaking multivariable regression analyses to determine the effect of race on progression to PDR.

Table 6

Duration of diabetes -Studies undertaking multivariable regression analyses to determine the effect of duration of diabetes on progression to PDR:

Table 7

Socio-economic status -Studies undertaking multivariable regression analyses to determine the effect of socio-economic status on progression to PDR.

Table 8

HbA1c -Studies undertaking multivariable regression analyses to determine the effect of HbA1c on progression to PDR.

Table 9

Diastolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of diastolic blood pressure on progression to PDR.

Table 10

Fasting plasma glucose -Studies undertaking multivariable regression analyses to determine the effect of fasting plasma glucose on progression to PDR.

Table 11

Systolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of systolic blood pressure on progression to PDR.

Table 12

Total cholesterol -Studies undertaking multivariable regression analyses to determine the effect of total cholesterol on progression to PDR.

Table 13

Triglycerides -Studies undertaking multivariable regression analyses to determine the effect of triglycerides on progression to PDR.

Table 14

Estimated glomerular filtration rate (eGFR) -Studies undertaking multivariable regression analyses to determine the effect of eGFR on progression to PDR.

Table 15

Diabetic retinopathy severity at baseline -Studies undertaking multivariable regression analyses to determine the effect of diabetic retinopathy severity at baseline on progression to PDR.

Table 16

Diabetic retinopathy features at baseline -Studies undertaking multivariable regression analyses to determine the effect of diabetic retinopathy features at baseline on progression to PDR.

Table 17

Body mass index (BMI) -Studies undertaking multivariable regression analyses to determine the effect of BMI on progression to PDR.

Table 18

Smoking -Studies undertaking multivariable regression analyses to determine the effect of smoking on progression to PDR.

Summary of the prognostic evidence for progression to diabetic macular oedema

Data from the NICE review

Table 19

Gender - Studies undertaking multivariable regression analyses to determine the effect of gender on progression to macular oedema.

Table 20

HbA1c -Studies undertaking multivariable regression analyses to determine the effect of HbA1c on progression to macular oedema.

Table 21

Diastolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of diastolic blood pressure on progression to macular oedema.

Table 22

Systolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of systolic blood pressure on progression to macular oedema.

Table 23

Total cholesterol -Studies undertaking multivariable regression analyses to determine the effect of total cholesterol on progression to macular oedema.

Table 24

Triglycerides -Studies undertaking multivariable regression analyses to determine the effect of triglycerides on progression to macular oedema.

Table 25

Estimated glomerular filtration rate (eGFR) -Studies undertaking multivariable regression analyses to determine the effect of eGFR on progression to macular oedema.

Table 26

Hypertension-Studies undertaking multivariable regression analyses to determine the effect of hypertension o on progression to macular oedema.

See Appendix E for full GRADE tables.

1.1.7. Economic evidence

1.1.7.1. Included studies

A single search was performed to identify published economic evaluations of relevance to any of the questions in this guideline update (Appendix B). This search retrieved 672 studies. Based on title and abstract screening, 671 of the studies could confidently be excluded for this review question. One study was excluded following the full-text review. No relevant health economic studies were included.

1.1.7.2. Excluded studies

See Appendix I for excluded studies and reasons for exclusion.

See the health economic study selection flow chart presented in Appendix F.

1.1.8. Summary of included economic evidence

No relevant health economic studies were identified to be included.

1.1.9. Economic model

Original health economic modelling was not prioritised for this review question.

1.1.10. Unit costs

No unit costs have been considered as part of this review question.

1.1.11. The committee’s discussion and interpretation of the evidence

1.1.11.1. The outcomes that matter most

The committee discussed that progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy or diabetic macular oedema are important outcomes as they indicate the worsening of retinopathy which leads to other serious consequences, such as vision loss.

The committee wanted to consider evidence for the progression of non-proliferative diabetic retinopathy to diabetic macular ischemia but found no relevant studies.

1.1.11.2. The quality of the evidence

The evidence for the risk factors predicting progression from proliferative diabetic retinopathy to diabetic retinopathy ranged from moderate to very low quality, with most of the downgrading due to studies being at high to moderate risk of bias. More information about the quality of individual studies can be found in the Cochrane review (Perais et al. 2020).

Three studies investigated clinical prediction factors for the progression of non-proliferative retinopathy to diabetic macular oedema for people with type 2 diabetes. The evidence ranged from moderate to low quality. Studies were most commonly downgraded for studies being at moderate risk of bias, or being partially applicable to the review, due to mixed populations being included rather than just people with non-proliferative retinopathy. One study reported that it adjusted for confounding factors, but did not report which factors were adjusted for, making it more difficult for the committee to interpret the results. There was no evidence on the prognostic factors for progression to diabetic macular oedema for people with type 1 diabetes.

The committee were unable to determine whether some factors, such as duration of diabetes, blood pressure and total cholesterol were risk factors for progression to proliferative diabetic retinopathy. For many of these factors, confidence intervals crossed the line of no effect. The committee noted that many of the studies did not adjust for important confounding factors, such as diabetic retinopathy severity at baseline. There was also variation in the reporting of important baseline characteristics, such as retinopathy severity at baseline and HbA1c. The committee were therefore limited in the recommendations that could be made due to uncertainty about the populations and methods used in the studies. They were also concerned that some of the confounding factors in the natural course of retinopathy were not being accounted for in the analysis.

Due the nature of the data, it was difficult to conduct meta-analysis. Each study differed according to the prognostic factors evaluated, time points of prognostic factor measurements and outcomes, and which confounding factors were adjusted for. As a result, much of the analysis was based on the results of single studies. Although some of the studies had very large sample sizes, the committee were concerned by other issues, such as either the choice of confounding factors that were adjusted for, or a lack of adjustment, and inconsistent results across different studies, The committee noted that there are a range of different factors that can influence the course of diabetic retinopathy, which made it difficult for the committee to be certain of which prognostic factors are most important to consider when assessing whether someone is at risk of progression.

There was no evidence for progression from non-proliferative diabetic retinopathy to diabetic macular ischemia. The committee thought this information was important and so this was included as part of a research recommendation (see Appendix J). This will enable recommendations to be made on this in future updates of the guideline.

1.1.11.3. Imprecision and clinical importance of effects

The committee noted that some of the results had wide confidence intervals. This imprecision made it hard to be certain of the effects of different prognostic factors. Due the nature of the data it was difficult to conduct meta-analysis and it was therefore difficult for the committee to determine which factors best predict a person’s risk of progression from non-proliferative diabetic retinopathy.

The committee agreed that the evidence for some of the prognostic factors for progression to proliferative diabetic retinopathy was precise enough to consider them risk factors for progression. Both severity of retinopathy and HbA1c levels were therefore listed as prognostic factors in the recommendations. Most of the evidence for other outcomes was based on single study analysis, with confidence intervals crossing the line of no effect. The committee could not be confident in whether these results indicated that other factors do not predict progression, or whether this was due to the limited number of studies for some comparisons, most of which had small sample sizes. A few results were from much larger studies, but the committee thought that the wide confidence intervals could partly reflect the factors that were selected for adjustment, rather than being a true reflection of the effect of a particular factor on progression of retinopathy. They therefore decided not to make further recommendations on progression to proliferative diabetic retinopathy. Instead, progression to proliferative diabetic retinopathy was included in the research recommendation (see Appendix J).

The evidence on diabetic macular oedema was mostly from small trials with a high degree of imprecision. A few studies included a larger number of participants, but for these studies, either confidence intervals crossed the line of no effect, or the committee had concerns about which factors were adjusted for in the analysis. Meta-analysis was not possible for any of the outcomes due to study heterogeneity, which further limited the conclusions that could be drawn.

1.1.11.4. Benefits and harms

Proliferative diabetic retinopathy

Higher HbA1c levels and severity of retinopathy at baseline were both shown to be predictors for the development of proliferative diabetic retinopathy in people with both type 1 and type 2 diabetes. The committee agreed that both factors are important and will help identify people who are at higher risk of progression.

There was also some evidence suggesting several markers for renal disease and triglyceride profiles in people with Type 1 diabetes were prognostic factors for progression. However, this evidence was low to very low quality, due to risk of bias in the included studies and inconsistency. The committee discussed that while this evidence was not high quality, their clinical knowledge and experience supported this being included in the recommendations as a risk factor that ophthalmologists should consider when deciding on a patient’s needs for follow-up.

The committee discussed how the evidence and their clinical experience suggests that people with non-proliferative diabetic retinopathy and type 1 or type 2 diabetes should be encouraged to manage modifiable risk factures. This includes maintaining adequate glucose control and blood pressure, to prevent progression to proliferative diabetic retinopathy. The committee also discussed the need for closer monitoring and communication across the multidisciplinary healthcare teams, such as diabetologist and ophthalmologists, who support people with diabetes. This will enable clinicians who are involved in a person’s wider diabetes management to access information about the status of a person’s diabetic eye disease and take this into account when they are considering future treatment and monitoring.

Diabetic macular oedema

Moderate and low-quality evidence showed that gender, increasing HBA1c (>8%), hypertension, and an estimated globular filtration rate of 30–45 were all predictors of progression to diabetic macular oedema. However, given the limited evidence base noted in the section above on the quality of the evidence, the committee did not think they could confidently recommend each of these factors as risk factors for progression. Instead, they decided to recommend that ophthalmologists should consider stage of retinopathy when deciding on follow-up and interventions, as this reflects a combination of the above factors, and other factors, which tend to develop over the course of disease.

Moderate quality evidence did not show blood pressure, cholesterol or triglycerides to be predictors of progression of diabetic macular oedema. However, the committee were concerned that the evidence for each prognostic factor came from single studies, the majority of which did not correct for stage of retinopathy at baseline. The committee noted that, in their clinical experience, higher blood pressure is often considered a risk factor for progression to macular oedema. This was considered important, as it is something that a patient can modify if they are aware of the risks of progression. Due to the very limited evidence base, progression to diabetic macular oedema was also included in the research recommendation (see Appendix J).

Given the limited evidence available, the committee decided to make general recommendations about risk factors for the progression of non-proliferative diabetic retinopathy to either proliferative diabetic retinopathy or diabetic macular oedema. This was based on a combination of the evidence for proliferative diabetic retinopathy and the committee’s clinical experience. Until there is more evidence to specify which factors make someone more at risk of progressing to either proliferative retinopathy or to macular oedema, they thought it was important to highlight factors that may be associated with progression in general. This will ensure that people are not overlooked for additional monitoring or treatment.

1.1.11.5. Cost effectiveness and resource use

No relevant economic evaluations were identified which addressed the cost effectiveness of the progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy or diabetic macular oedema. The committee discussed that ophthalmologists should have access to a patient’s HbA1c and blood pressure results for discussion with the patient. Educating the patient with information on how they can lower HbA1c, and blood pressure can give the patient the opportunity to reduce their risk of progression to proliferative diabetic retinopathy or diabetic macular oedema. This could lead to a reduction in resource impact by delaying or preventing progression of disease which has considerable cost and quality of life implications.

1.1.12. Recommendations supported by this evidence review

This evidence review supports Recommendations 1.1.3 to 1.1.5 and the research recommendation on prognostic factors for the progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy, diabetic macular oedema, or macular ischemia.

1.1.13. References – included studies

1.1.13.1. Effectiveness

Studies included from the NICE review

Hammes, H.-P., Welp, R., Kempe, H.-P. et al (2015) Risk factors for retinopathy and DME in type 2 diabetes-results from the German/Austrian DPV database. PLoS ONE 10(7): e0132492 [PMC free article: PMC4503301] [PubMed: 26177037]
Hsieh, Yi-Ting, Tsai, Meng-Ju, Tu, Shih-Te et al (2018) Association of Abnormal Renal Profiles and Proliferative Diabetic Retinopathy and Diabetic Macular Edema in an Asian Population With Type 2 Diabetes. JAMA ophthalmology 136(1): 68–74 [PMC free article: PMC5833599] [PubMed: 29167896]
Lobo, Conceicao, Pires, Isabel, Alves, Dalila et al (2018) Subclinical Macular Edema as a Predictor of Progression to Central-Involved Macular Edema in Type 2 Diabetes. Ophthalmic research 60(1): 18–22 [PubMed: 29510401]

Included systematic review (Cochrane review)

Perais, J, Agarwal, R, Evans, JR, Loveman, E, Colquitt, JL, Owens, D, Hogg, R, Lawrenson, JG, Takwoingi, Y, Lois, N. Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy. Cochrane Database of Systematic Reviews 2020, Issue 11. Art. No.: CD013775. DOI: 10.1002/14651858.CD013775. [PMC free article: PMC9943918] [PubMed: 36815723] [CrossRef]

Studies included from the Cochrane review (Perais et al., 2020)

Cho 2019 {published data only}
Cho, A, Noh, JW, Kim, J. Progression of diabetic retinopathy and declining renal function in patients with type 2 diabetes. Journal of the American Society of Nephrology 2019;30:507.
Gange 2021 {published data only}
Gange, WS, Lopez, J, Xu, BY, Lung, K, Seabury, SA, Toy, BC. Incidence of Proliferative Diabetic Retinopathy and Other Neovascular Sequelae at 5 Years Following Diagnosis of Type 2 Diabetes. Diabetes Care 2021;44(11):2518–26. [PMC free article: PMC8546279] [PubMed: 34475031]
Grauslund 2009a {published data only}
Gaedt Thorlund, M, Borg Madsen, M, Green, A, Sjølie, AK, Grauslund, J. Is smoking a risk factor for proliferative diabetic retinopathy in type 1 diabetes? Ophthalmologica 2013;230(1):50–4. [PubMed: 23751972]
Grauslund, J, Green, A, Sjølie, AK. Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients. Diabetologia 2009;52(9):1829–35. [PubMed: 19593541]
Harris 2013 {published data only}
Harris, NK, Talwar, N, Gardner, TW, Wrobel, JS, Herman, WH, Stein, JD. Predicting development of proliferative diabetic retinopathy. Diabetes Care 2013;36(6):1562–8. [PMC free article: PMC3661803] [PubMed: 23275374]
Hsieh 2018 {published data only}
Hsieh, Y-T, Hsieh, M-C. Time-sequential correlations between diabetic kidney disease and diabetic retinopathy in type 2 diabetes - an 8-year prospective cohort study. Acta Ophthalmologica 2021;99(1):e1–6. [PubMed: 32567151]
Hsieh, Y-T, Tsai, M-J, Tu, S-T, Hsieh, M-C. Association of Abnormal Renal Profiles and Proliferative Diabetic Retinopathy and Diabetic Macular Edema in an Asian Population With Type 2 Diabetes. JAMA Ophthalmology 2018;136(1):68–74. [PMC free article: PMC5833599] [PubMed: 29167896]
Janghorbani 2000 {published data only}
Janghorbani, M, Jones, RB, Allison, SP. Incidence of and risk factors for proliferative retinopathy and its association with blindness among diabetes clinic attenders. Ophthalmic Epidemiology 2000;7(4):225–41. [PubMed: 11262670]
Jeng 2016 {published data only}
Jeng, C-J, Hsieh, Y-T, Yang, C-M, Yang, C-H, Lin, C-Li, Wang, IJ. Diabetic Retinopathy in Patients with Diabetic Nephropathy: Development and Progression. PloS One 2016;11(8):e0161897. [PMC free article: PMC5001700] [PubMed: 27564383]
Kalter-Leibovici 1991 {published data only}
Kalter-Leibovici, O, Van Dyk, DJ, Leibovici, L, Loya, N, Erman, A, Kremer, I, et al Risk factors for development of diabetic nephropathy and retinopathy in Jewish IDDM patients. Diabetes 1991;40(2):204–10. [PubMed: 1991571]
Keen 2001 {published data only}
Keen, H, Lee, ET, Russell, D, Miki, E, Bennett, PH, Lu, M. The appearance of retinopathy and progression to proliferative retinopathy: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44 Suppl 2:S22–30. [PubMed: 11587046]
Kim 1998 {published data only}
Kim, HK, Kim, CH, Kim, SW, Park, JY, Hong, SK, Yoon, YH, et al Development and progression of diabetic retinopathy in Koreans with NIDDM. Diabetes Care 1998;21(1):134–8. [PubMed: 9538984]
Kim 2014 {published data only}
Kim, YJ, Kim, JG, Lee, JY, Lee, KS, Joe, SG, Park, JY, et al Development and progression of diabetic retinopathy and associated risk factors in Korean patients with type 2 diabetes: the experience of a tertiary center. Journal of Korean Medical Science 2014;29(12):1699–705. [PMC free article: PMC4248594] [PubMed: 25469073]
Klein 1984 {published data only}
Klein, BE, Davis, MD, Segal, P, Long, JA, Harris, WA, Haug, GA, et al Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 1984;91(1):10–7. [PubMed: 6709313]
Lee 1992 {published data only}
Lee, ET, Lee, VS, Lu, M, Russell, D. Development of proliferative retinopathy in NIDDM: a follow-up study of American Indians in Oklahoma. Diabetes 1992;41(3):359–67. [PubMed: 1551496]
Lee 2017a {published data only}
Lee, CS, Lee, AY, Baughman, D, Sim, D, Akelere, T, Brand, C, et al The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group: Report 3: Baseline Retinopathy and Clinical Features Predict Progression of Diabetic Retinopathy. American Journal of Ophthalmology 2017;180(3oq, 0370500):64–71. [PMC free article: PMC5608549] [PubMed: 28572062]
Lee 2021 {published data only}
Lee, CC, Hsing, SC, Lin, YT, Lin, C, Chen, JT, Chen, YH, et al The importance of close follow-up in patients with early-grade diabetic retinopathy: A Taiwan population-based study grading via deep learning model. International Journal of Environmental Research and Public Health 2021;18(8):9768. [PMC free article: PMC8470712] [PubMed: 34574686]
Lloyd 1995 {published data only}
Lloyd, CE, Becker, D, Ellis, D, Orchard, TJ. Incidence of complications in insulin-dependent diabetes mellitus: a survival analysis. American Journal of Epidemiology 1996;143(5):431–41. [PubMed: 8610658]
Lloyd, CE, Klein, R, Maser, RE, Kuller, LH, Becker, DJ, Orchard, TJ. The progression of retinopathy over 2 years: the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. Journal of Diabetes Complications 1995;9(3):140–8. [PubMed: 7548977]
McCarty 2003 {published data only}
McCarty, DJ, Fu, CL, Harper, CA, Taylor, HR, McCarty, CA. Fiveyear incidence of diabetic retinopathy in the Melbourne Visual Impairment Project. Clinical & Experimental Ophthalmology 2003;31(5):397–402. [PubMed: 14516426]
Nelson 1989 {published data only}
Nelson, RG, Wolfe, JA, Horton, MB, Pettitt, DJ, Bennett, PH, Knowler, WC. Proliferative retinopathy in NIDDM: incidence and risk factors in Pima Indians. Diabetes 1989;38(4):435–40. [PubMed: 2925007]
Okudaira 2000 {published data only}
Okudaira, M, Yokoyama, H, Otani, T, Uchigata, Y, Iwamoto, Y. Slightly elevated blood pressure as well as poor metabolic control are risk factors for the progression of retinopathy in early-onset Japanese Type 2 diabetes. Journal of Diabetes and its Complications 2000;14(5):281–7. [PubMed: 11113692]
Porta 2001 {published data only}
Porta, M, Sjoelie, AK, Chaturvedi, N, Stevens, L, Rottiers, R, Veglio, M, et al Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia 2001;44(12):2203–9. [PubMed: 11793022]
Roy 2006 {published data only}
Roy, MS, AEouf, M. Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus: the New Jersey 725. Archives of Ophthalmology 2006;124(9):1297–306. [PubMed: 16966625]
Roy, MS, Klein, R, Janal, MN. Retinal venular diameter as an early indicator of progression to proliferative diabetic retinopathy with and without high-risk characteristics in African Americans with type 1 diabetes mellitus. Archives of Ophthalmology 2011;129(1):8–15. [PubMed: 21220623]
Skrivarhaug 2006 {published data only}
Skrivarhaug, T, Fosmark, DS, Stene, LC, Bangstad, HJ, Sandvik, L, Hanssen, KF, et al Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes: a 24-year follow-up study. Diabetologia 2006;49(10):2281–90. [PubMed: 16955208]
WESDR {published data only}
Cruickshanks, KJ, Moss, SE, Klein R Klein, BE. Physical activity and the risk of progression of retinopathy or the development of proliferative retinopathy. Ophthalmology 1995;102(8):1177–82. [PubMed: 9097744]
Klein, BE K, Klein, R, Moss, SE, Palta, M. A cohort study of the relationship of diabetic retinopathy to blood pressure. Archives of Ophthalmology 1995;113(5):601–6. [PubMed: 7748130]
Klein, R, Klein, BE, Jensen, SC, Moss, SE. The relation of socioeconomic factors to the incidence of proliferative diabetic retinopathy and loss of vision. Ophthalmology 1994;101(1):68–76. [PubMed: 8302566]
Klein, R, Klein, BE, Moss, SE, Cruickshanks, KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Archives of Internal Medicine 1994;154(19):2169–78. [PubMed: 7944837]
Klein, R, Klein, BE, Moss, SE, Cruickshanks, KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14- year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 1998;105(10):1801–15. [PubMed: 9787347]
Klein, R, Klein, BE, Moss, SE, Cruickshanks, KJ. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Archives of Ophthalmology 1994;112(9):1217–28. [PubMed: 7619101]
Klein, R, Klein, BE, Moss, SE, Davis, MD, DeMets, DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988;260(19):2864–71. [PubMed: 3184351]
Klein, R, Klein, BE, Moss, SE, Davis, MD, DeMets, DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology 1989;107(2):237–43. [PubMed: 2916977]
Klein, R, Klein, BE, Moss, SE, Davis, MD, DeMets, DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Archives of Ophthalmology 1989;107(2):244–9. [PubMed: 2644929]
Klein, R, Klein, BE, Moss, SE. Is obesity related to microvascular and macrovascular complications in diabetes? The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Archives of Internal Medicine 1997;157(6):650–6. [PubMed: 9080919]
Klein, R, Klein, BE, Moss, SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Annals of Internal Medicine 1996;124(1 Pt 2):90–6. [PubMed: 8554220]
Klein, R, Klein, BE, Moss, SE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XVI. The relationship of C-peptide to the incidence and progression of diabetic retinopathy. Diabetes 1995;44(7):796–801. [PubMed: 7789648]
Klein, R, Klein, BE K, Moss, SE, Davis, MD, DeMets, DL. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Archives of Internal Medicine 1989;149(11):2427–32. [PubMed: 2684072]
Klein, R, Klein, BE K, Moss, SE, Wong, TY, Hubbard, L, Cruickshanks, KJ, et al The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Archives of Ophthalmology 2004;122(1):76–83. [PubMed: 14718299]
Klein, R, Klein, BE K, Moss, SE, Wong, TY. Retinal vessel caliber and microvascular and macrovascular disease in type 2 diabetes: XXI: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 2007;114(10):1884–92. [PubMed: 17540447]
Klein, R, Knudtson, MD, Lee, KE, Gangnon, R, Klein, BE K. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 2008;115(11):1859–68. [PMC free article: PMC2761813] [PubMed: 19068374]
Klein, R, Meuer, SM, Moss, SE, Klein, BE. Retinal microaneurysm counts and 10-year progression of diabetic retinopathy. Archives of Ophthalmology 1995;113(11):1386–91. [PubMed: 7487599]
Klein, R, Meuer, SM, Moss, SE, Klein, BE. The relationship of retinal microaneurysm counts to the 4-year progression of diabetic retinopathy. Archives of Ophthalmology 1989;107(12):1780–5. [PubMed: 2597068]
Klein, R, Moss, SE, Klein, BE K. Is gross proteinuria a risk factor for the Incidence of proliferative diaberic retinopathy? Ophthalmology 1993;100(8):1140–6. Moss SE, Klein R, Klein BE. Association of cigarette smoking with diabetic retinopathy. Diabetes Care 1991;14(2):119–26. Moss SE, [PubMed: 8341493]
Klein, R, Klein, BE. Cigarette smoking and tenyear progression of diabetic retinopathy. Ophthalmology 1996;103(9):1438–42. Moss SE, Klein R, Klein BE. Ocular factors in the incidence and progression of diabetic retinopathy. Ophthalmology 1994;101(1):77–83. [PubMed: 8302567]
Moss, SE, Klein, R, Klein, BE K. The association of alcohol consumption with the incidence and progression of diabetic retinopathy. Ophthalmology 1994;101(12):1962–8. [PubMed: 7997335]

1.1.13.2. Economic

No economic studies were included.

Appendices

Appendix A. Review protocols

Review protocol for prognostic factors for the progression of non-proliferative diabetic retinopathy in people with diabetic retinopathy to:

proliferative diabetic retinopathy
diabetic macular oedema
diabetic macular ischaemia

Download PDF (221K)

Appendix B. Literature search strategies

Cost effectiveness searches

A broad search covering the diabetic retinopathy population was used to identify studies on cost effectiveness. The searches were run in February 2022.

Limits and restrictions

English language limits were applied in adherence to standard NICE practice and the review protocol.

Limits to exclude, comment or letter or editorial or historical articles or conference abstract or conference paper or "conference review" or letter or case report were applied in adherence to standard NICE practice and the review protocol.

The limit to remove animal studies in the searches was the standard NICE practice, which has been adapted from: Dickersin, K., Scherer, R., & Lefebvre, C. (1994). Systematic Reviews: Identifying relevant studies for systematic reviews. BMJ, 309(6964), 1286 [PMC free article: PMC2541778] [PubMed: 7718048].

Search filters

Cost utility

The NICE cost utility filter was applied to the search strategies in MEDLINE and Embase to identify cost-utility studies.

Hubbard W, et al Development of a validated search filer to identify cost utility studies for NICE economic evidence reviews. NICE Information Services.

Cohort studies

For the modelling, cohort/registry terms were used from the NICE observational filter that was developed in-house.

The NICE Organisation for Economic Co-operation and Development (OECD) filter was also applied to search strategies in MEDLINE and Embase.

Ayiku, L., Hudson, T., et al (2021)The NICE OECD countries geographic search filters: Part 2 – Validation of the MEDLINE and Embase (Ovid) filters. Journal of the Medical Library Association) [PMC free article: PMC8608218] [PubMed: 34858087]

Cost effectiveness search strategies

Download PDF (157K)

Appendix C. Prognostic evidence study selection

Download PDF (101K)

Appendix D. Prognostic evidence

D.1. Studies included from the NICE search

Download PDF (199K)

D.2. Cochrane Systematic Review

Download PDF (196K)

D.3. Studies included from the Cochrane systematic review

For full evidence tables for the studies included from the Cochrane review, see the section on Characteristics of included studies in Perais et al. 2020.

Appendix E. GRADE tables

E.1. Prognostic evidence for people progressing to proliferative diabetic retinopathy

The quality assessment for prognostic factors for people progressing to proliferative diabetic retinopathy can be seen in the Cochrane review (Perais et al. 2020).

E.2. Prognostic evidence for people progressing to diabetic macular oedema

Download PDF (154K)

Appendix F. Economic evidence study selection

Download PDF (100K)

Appendix G. Economic evidence tables

There are no included studies for this review question.

Appendix H. Health economic model

Original health economic modelling has not been conducted for this review question.

Appendix I. Excluded studies

Clinical evidence

Table

- outcome/End point do not match that specified in the protocol Mixed population

Economic evidence

Table

Appendix J. Research recommendations - full details

J.1. Research recommendation

J.2. What are the prognostic factors for the progression of non proliferative diabetic retinopathy to proliferative diabetic retinopathy, diabetic macular oedema and macular ischemia?

J.3. Why this is important

Progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy, diabetic macular oedema or diabetic macular ischemia can have negative consequences for people with diabetes. Progression also results in people needing more treatments, which impacts on both patients and the NHS. Some studies have considered the risk factors for progression of non-proliferative diabetic retinopathy, but there is limited high-quality evidence to help determine which factors are the biggest risk for progression. It is important to identify which factors, or combination of factors, are accurate indicators of disease progression and can be used in clinical practice in decision-making.

J.4. Rationale for research recommendation

Download PDF (131K)

J.5. Modified PICO table

Download PDF (123K)

Final

Evidence reviews underpinning recommendations 1.1.3 to 1.1.5 and research recommendation 2 in the NICE guideline

These evidence reviews were developed by NICE

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK607354PMID: 39348480

Table 1Summary of the PICO

Population	People with non-proliferative diabetic retinopathy
Prognostic factor	Age Gender Ethnicity Socio-economic status Smoking habits presence/absence of cardiovascular disease cerebrovascular disease nephropathy and specifically chronic kidney failure (defined as estimated glomerular filtration rate (GFR) of < 60 mL/min/1.73 m2), peripheral neuropathy and specifically foot ulcers, amputation body mass index (BMI) neck/waist circumference glycated haemoglobin blood pressure cholesterol and triglyceride Anatomical changes in the retina (for example venous beading, cotton wool spots, venous looping, intraretinal microvascular abnormality, microaneurysms, exudates, dot-blot haemorrhages, neovascularisation) Sleep apnoea Duration of diabetes Learning disability or mental health issue Pregnancy
Reference standard	Progression to: Proliferative diabetic retinopathy (treatment for diabetic retinopathy will be taken as a surrogate measure of progression). Diabetic macular oedema (treatment for diabetic macular oedema will be taken as a surrogate measure of development of macular oedema) Diabetic macular ischaemia
Outcomes	Outcomes to be predicted: Proliferative diabetic retinopathy Diabetic macular oedema Diabetic macular ischaemia Adjusted odds ratios, risk ratios, hazard ratios will be used as a measure of association between the predictors and reference standard (outcomes to be predicted) Outcomes will be reported at the latest time point reported by the study.

Table 2Prognostic factors for progression to proliferative diabetic retinopathy included from Cochrane review

Study	Study type and follow-up time	Population	Prognostic factors
Cho 2019 (n= 1527)	Retrospective cohort Duration of follow-up: 4 years	Inclusion criteria: T2D underwent fundus photographic examinations for DR. renal profiles were studied between August 2006 and February 2014. Exclusion criteria: Estimated glomerular filtration rate < 15 ml/min/1:73 m2 without follow-up renal profiles fundus exam obtained more than 3 months after the first evaluation.	eGFR Age at baseline Diabetes duration Fasting plasma glucose HbA1c
Gange 2021 (n=277,401)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: insured patients aged ≥18 years. newly diagnosed T2D; continuous enrolment for 12-months without a diabetes diagnosis any diabetes medication use. Exclusion criteria: Concurrent pregnancy gestational diabetes T1D use of an insulin pump diagnosis of diabetic eye disease prior to the diagnosis of diabetes.	Age at DM diagnosis Gender Race Socio-economic status Hypertension Smoking history Insulin HbA1c
Grauslund 2009a (n= 573)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: All T1D patients from Fyn County, Denmark, DM onset before 30 years of age, identified based on insulin prescription as of 1 July 1973. Exclusion criteria: Not reported.	Systolic BP Diastolic BP BMI DR Status at BL Maculopathy Diabetes duration HbA1c Proteinuria Smoking history
Harris 2013 (n=4617)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: New diagnosis of NPDR after first year in registry (point of baseline) aged ≥ 30 years. ≥ 2 registrations as having diagnosis of DM; continuous enrolment in registry. ≥1 visit to an ophthalmologist or optometrist during first year of registration. no signs of NPDR or PDR; ≥ one record of HbA1c following baseline date. Exclusion criteria: In registry <1 year; not in registry continuously any record of PDR prior to index date.	Insulin Age at baseline Gender Race
Hsieh 2018 (n=2135)	Retrospective cohort Duration of follow-up: 5 year	Inclusion criteria: Patients who received a diagnosis of T2D and underwent treatment between April 2002 and September 2004. Exclusion criteria: Lost to follow-up within 6-months. Ungradable image results from both eyes at baseline.	eGFR
Janghorbani 2000 (n=3482)	Retrospective cohort Duration of follow-up:	Inclusion criteria: NIDDM or IDDM free of PDR (including those with no retinopathy and those with NPDR at registration) complete data available. Exclusion criteria: Secondary diabetes type of diabetes unknown	Diabetes duration HbA1c Systolic BP
Jeng 2016 (n=53453)	Retrospective cohort Duration of follow-up:	Inclusion criteria: Diabetic nephropathy (DN) cohort≥ 18-year-old patients with DM plus DN diagnosed between 01/01/00 and 31/12/10. Non-DN cohort: diagnosis of DN not made during 01/01/00 and 31/12/10. Exclusion criteria: Not reported.	Gender Age at baseline Hypertension History of CVD DR Status at BL
Kalter-Leibovici 1991 (n=330)	Retrospective cohort Duration of follow-up:	Inclusion criteria: Diabetes type: T1D. All Jewish patients attending centre with early-onset IDDM before 30 years of age. DM duration of ≥ 10 yrs. Exclusion criteria: Not reported.	Socio-economic status HbA1c Diabetes duration Race
Keen 2001 (n=4483)	Retrospective cohort Duration of follow-up:	Inclusion criteria: Diabetes type: T1D and T2D. The study protocol required equal numbers of men and women with diabetes, sampled from three age bands within the range 35 to 54 years. Exclusion criteria: Not reported.	Gender Age at baseline Diabetes duration Systolic BP Diastolic BP Cholesterol BMI Smoking history Insulin Fasting plasma glucose Age at DM diagnosis Diabetes type
Kim 1998 (n=56)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Diabetes type: T2D. Pts attending a university hospital (the Asan Medical Centre) in Seoul, Korea NIDDM diagnosis no episodes of ketoacidosis, a diagnosis of diabetes after 30 years of age and treatment by diet and/or oral hypoglycaemic agents fasting serum C-peptide values >0.30 nmol/L in patients using insulin Exclusion criteria: Not reported.	Cholesterol Triglyceride HbA1c Diabetes duration Age at baseline BMI
Kim 2014 (n=452)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Diabetes type: T2D Patients who were diagnosed and followed for more than 5 years annually or more often at a hospital-based dia-betic clinic (Asan Medical Centre, Seoul, Korea) Exclusion criteria: PDR at the initial examination, concomitant ocular disease other than DR history of ocular trauma intraocular surgery	Age at baseline Diabetes duration BMI Fasting blood sugar HbA1c SD of HbA1c Systolic BP Diastolic BP Cholesterol Triglyceride
Klein 1984 (n=191)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Diabetes type: T1D On insulin since DM diagnosis if asymptomatic and diagnosed through routine examination must have become symptomatic and taken insulin within one year of diagnosis ≥ 5 years duration; under care of cooperating GPs for at least 2/3 of the duration of DM. Exclusion criteria: Overweight; ≥ 50 years.	DR Status at BL DR Features
Lee 1992 (n=354)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Diabetes type: T2D. NIDDM (no further description); Oklahoma Indians examined at the Indian Health Service facilities in Oklahoma FPG >7.8 mmol (140 mg/dl) or a 2-hour post-load blood glucose level >11.1 mmol (200 mg/dl); diagnoses of DM between 1937 and 1980. Exclusion criteria: PDR at baseline.	Diabetes duration Cholesterol Systolic BP Age at baseline Type of diabetes treatment Systolic BP Age at DM diagnosis
Lee 2017a (n=32553)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: First-time presenters to eye providers after being referred from the UK national DR screening program. at least 2 DR assessments. Exclusion criteria: Anti-vascular endothelial growth factor injections during study period eyes with neovascularization at baseline were excluded from survival analyses.	DR Status at BL DR Features
Lee 2021 (n=2626)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: T2D with more than two fundus colour photography tests. Exclusion criteria: Without T2D no HbA1c or FPG tests within 14 days of the study start. PDR.	DR Status at BL DR Features
Lloyd 1995 (n=496)	Retrospective cohort Duration of follow-up:NR	Inclusion criteria: Childhood-onset < 17 years Hospital of Pittsburgh between January 1950 and May 1980 Exclusion criteria: Not reported.	Glycosylated haemoglobin Triglyceride Diastolic BP Diabetes duration DR Status at BL
Nelson 1989	prospective cohort Duration of follow-up: NR	Inclusion criteria: all diabetic people who lived in the Gila River Indian Community at any time between 13 October 1983 and 30 November 1987; whose heritage was at least 50% Pima, Papago, or a mixture of these closely related tribes; and who had undergone biennial research examinations. Exclusion criteria: not reported	HbA1c DR severity at baseline Gender
Okudaira 2000 (n=527)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Patients who first visited the outpatient clinic between 1980 and 1989 patients exhibited neither proteinuria nor PDR at the first visit; patients who were seen at the clinic for at least 1 year patients who underwent fundus examination through dilated pupils by ophthalmologists at least once a year during the follow-up. Exclusion criteria: Not reported.	Age at DM diagnosis Age at baseline Diabetes duration BMI Smoking history HbA1c Diastolic BP Systolic BP Cholesterol Triglyceride
Porta 2001 (n=3250)	Retrospective cohort Duration of follow-up: NR	inclusion criteria: Diagnosed T1D < 36 years. insulin within 1 year onset age 15–60 years. Exclusion criteria: Centre drop-out no retinal photo at baseline at follow-up PDR at baseline.	Diastolic BP Age at DM diagnosis Diabetes duration HbA1c DR Status at BL
Roy 2006 (n=725)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: African Americans with T1D; Treated with insulin before 30 years of age. receiving insulin at time of study participated in the New Jersey 725 study 1993–1998. Exclusion criteria: T2D; diagnosed after 30 years; maturity-onset diabetes of youth.	HbA1c age at baseline Hypertension Diastolic BP
Skrivarhaug 2006 (n=368)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: All new-onset cases of T1D in Norway in children below 15 years of age between 1973 and 1982 examined for DR at baseline. Exclusion criteria: Not reported.	Gender Diabetes duration Mean age at PDR diagnosis Mean diabetes duration at PDR diagnosis HbA1c Triglyceride DR Status at BL
WESDR (n=2366)	Retrospective cohort Duration of follow-up: NR	Inclusion criteria: Younger-onset group: IDD before 30 years. Older onset: Diagnosed with DM at 30 years or older and diagnosis. postprandial serum glucose level of at least 11.1 mmol/L a fasting serum glucose level of 7.8 mmol/L or greater on at least two occasions. Exclusion criteria: Not reported.	Diabetes duration Age Gender Diabetes duration HbA1c Systolic BP Diastolic BP BMI Triglyceride Smoking history

Table 3Included studies of prognostic factors for progression to diabetic macular oedema (NICE review)

Study

Study type and follow-up time

Population

Prognostic factors

Hammes, 2015 (n= 64784)

Prospective cohort
Duration of follow-up: NR

Inclusion criteria:

Type 2 diabetes
age at disease onset was above 40 years.
at least one retinal examination had been documented.

Exclusion criteria:

younger than 40 years of age

Age
Diabetes Duration
Gender
Hba1c Hypertension
Smoking

Hsieh 2018 (n= 2135)

prospective cohort
Duration of follow-up: 8-year

Inclusion criteria:

Type 2 Diabetes.
Patients With Gradable Image

Exclusion criteria:

Patients with ungradable image results from both eyes at baseline

Estimated Glomerular Filtration Rate (eGFR)
Body Mass Index
Systolic Blood Pressure (SBP),
Diastolic Blood Pressure
Haemoglobin A1c (Hba1c)
Fasting Glucose Level
Total Cholesterol Level
Triglyceride Level

Lobo, 2018 (n=205)

Prospective cohort
Duration of follow-up: 2 years

Inclusion criteria:

Diabetes type 2
aged over 35 years,
mild NPDR (levels 20–35, according (ETDRS) diabetic retinopathy severity scale)
best-corrected visual acuity (BCVA) >20/25 on the ETDRS chart
HbA1C ≤11%, with no previous treatment with laser or anti-VEGF or steroid intravitreal injection
no other retinal vascular disease or glaucoma
inadequate ocular media and/or pupil dilatation
that did not permit good-quality fundus photography.

Exclusion criteria:

Not reported

Age
Gender
HbA1c
Systolic Blood Pressure
Diastolic Blood Pressure
Cholesterol
Triglycerides

Table 4Gender - Studies undertaking multivariable regression analyses to determine the effect of gender on progression to proliferative diabetic retinopathy

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes (Male vs female)
RR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 4 years
1 Nelson 1989	953	Adjusted RR: 1.5 (0.7 3.4)	Moderate
Type 1 and 2 diabetes (Male vs female)
1 Lee 2017	32,553	Adjusted HR: 0.92 (0.71–1.19)¹	Moderate
HR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 5 years
1 Harris 2013	4,617	Adjusted HR: 1.08 (0.94–1.22)	Moderate
HR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 5 years (Female vs male)
1 Jeng 2016	53,453	Adjusted HR: 0.99 (0.85–1.15)	Moderate

Table 5Race -Studies undertaking multivariable regression analyses to determine the effect of race on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes African American race vs. Caucasian HR/OR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 5 years
1 Arfken 1998	312	Adjusted OR: 0.73 (0.30–1.78)	Very low
Type 2 Diabetes
Non-Caucasian vs. Caucasian
1 Lee 2017a	32,553	Adjusted HR: 0.94 (0.89–1.00)	Very low
Type 1 and type 2 diabetes
Black
Harris 2013	4617	Adjusted HR: 1.29 (0.92–1.82)	Very low
Latino
Harris 2013	4617	Adjusted HR: 1.12 (0.76–1.65)	Very low
Asian
Harris 2013	4617	Adjusted HR: 1.35 (0.73–2.49)	Very low

Table 6Duration of diabetes -Studies undertaking multivariable regression analyses to determine the effect of duration of diabetes on progression to PDR:

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes RR >1 indicates risk factor of progression to proliferative diabetic retinopathy
Lloyd 1995	496	Adjusted RR: 1.03 (0.94–1.12)	Very low
4–7 years vs. <4 years
Janghorbani 2000	1349	Adjusted RR: 0.78 (0.43–1.41)	Very low
8–11 years vs. <4 years
Janghorbani 2000	1349	Adjusted RR: 1.95 (1.23–3.09)	Very low
≥12 years vs. <4 years
Janghorbani 2000	1349	Adjusted RR: 3.05 (2.09–4.45)	Very low
Increasing duration of diabetes
Kalter-Leibovici 1991	330	Adjusted OR: 1.20 (1.1–1.3)	Very low
Per 10 years
Grauslund 2009a	573	Adjusted OR: 0.69 (0.35–1.36)	Very low
Type 2 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 5 years
Mean duration of diabetes at 2 years follows up
Gui 2013	205	Adjusted OR:1.18 (1.13–1.25)	Very low
12 years vs. <4 years, taking insulin
Janghorbani 2000	2133	Adjusted OR: 1.77 (1.15–2.72)	Very low
12 years vs. <4 years, not taking insulin
Janghorbani 2000	2133	Adjusted OR: 1.37 (0.83–2.26)	Very low
Type 1 and type 2 diabetes
Duration of diabetes 8–11 years
Janghorbani 2000	3482	Adjusted RR: 1.42 (1.10–1.83)	Very low
Duration of diabetes ≥12 years
Janghorbani 2000	4483	Adjusted RR 1.95 (1.58–2.39)	Very low

Table 7Socio-economic status -Studies undertaking multivariable regression analyses to determine the effect of socio-economic status on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 4 years. (Per 10-point increase) Females Per 10-point increase
WESDR	996	Adjusted OR: 0.78 (0.52–1.18)	Very low
Klein 1994	996	Adjusted OR: 0.79 (0.46–1.37)	Very low
OR >1 indicates risk factor of progression to proliferative diabetic retinopathy at 4 years. (Per 10-point increase) Males Per 10-point increase
WESDR	1370	Adjusted OR: 0.84 (0.58–1.23)	Very low
Klein 1994	1370	Adjusted OR: 0.88 (0.55–1.41)¹	Very low

Table 8HbA1c -Studies undertaking multivariable regression analyses to determine the effect of HbA1c on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes OR/RR>1 indicates risk factor of progression to proliferative diabetic retinopathy. Top quartile compared to other three quartiles
Lloyd 1995	496	Adjusted RR: 5.75 (1.54–21.4)	Moderate
HbA1c Per 1% increase
Klein 1984	996	Adjusted RR: 1.5 (1.4–1.8)	Moderate
HbA1c ≥11 relative to <11%
Janghorbani 2000	1349	Adjusted RR: 1.32 (1.22–1.43⁾	Moderate
HbA1c Per 1% increase
Roy 2006	725	Adjusted OR: 1.32 (1.22–1.43)	Moderate
HbA1c Per 2% increase
Arfken 1998	312	Adjusted OR: 1.92 (1.36–2.7)	Moderate
HbA1c Per 1% increase At 10 years
WESDR Klein 1994	334	Adjusted OR: 1.9 (1.7–2.2)	Moderate
At 14 years
WESDR Klein 1994	996	Adjusted OR: 1.81 (1.6–2.05)	Moderate
At 24 years
WESDR Klein 1994	955	Adjusted HR: 1.38 (1.31–1.46)	Moderate
Type 2 diabetes
Older onset taking insulin Per 1% increase
WESDR Klein 1994	1370	Adjusted OR: 1.30 (1.00–1.60)	Moderate
HbA1c Per 1% increase
Cho 2019	1527	Adjusted OR: 1.11 (0.93–1.32)	Moderate
Mean HbA1c during follow-up
Kim 1998	228	Adjusted RR: 1.30 (1.04–1.61)	Moderate
Maximum >9% vs <6.5%
Gange 2021	71815	Adjusted OR: 2.10 (1.64–2.69)	Moderate
HR >1 indicates higher HbA1c is a risk factor of progression to proliferative diabetic retinopathy
Mean HbA1c
Okudaira 2000	527	Adjusted HR: 1.43 (1.23–1.67)	Moderate
HbA1c Per one SD
Lee 2021	2623	Adjusted: HR: 1.09 0.97–1.22	Moderate
HbA1c Per unit increase
Kim 2014	452	Adjusted HR: 1.19 (1.10–1.46)	Moderate
Older-onset, (40 >) taking insulin and Older-onset, (40>) not taking insulin Per 1% increase
WESDR Klein 1994	996	Insulin: Adjusted OR: 0.79 (0.46–1.37)⁶ Non-insulin Adjusted OR: 0.78 (0.52–1.18)⁶	Moderate
10-year HbA1c
Kalter-Leibovici 1991	330	Adjusted OR: 1.9 (1.4–2.5)	Moderate
Type 1 and type 2 diabetes
With increasing HbA1c at 5 years
Harris 2013	4617	Adjusted HR: 1.14 (1.07–1.21)	Moderate
HbA1c ≥11
Janghorbani 2000	3482	Adjusted RR 1.33 (1.13–1.53)	Moderate

Table 9Diastolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of diastolic blood pressure on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes
OR>1 indicates risk factor of progression to proliferative diabetic retinopathy
79 to ≥86 mmHg
Roy 2006	725	Adjusted OR: 2.5 (1.04–6.00)	Very low
Per 10 mmHg Per increase in one year
Grauslund 2009a	573	Adjusted OR: 1.31 (0.86–1.99)	Very low
Type 2 diabetes
Per unit increase
Okudaira 2000	527	Adjusted HR: 1.15 (1.01–1.31)	Very low
Per one SD
Lee 2021	2623	Adjusted HR: 1.03 (1.00–1.05)	Very low

Table 10Fasting plasma glucose -Studies undertaking multivariable regression analyses to determine the effect of fasting plasma glucose on progression to PDR

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes

OR>1 indicates Fasting plasma glucose is a risk factor of progression to proliferative diabetic retinopathy.

Fasting plasma glucose

Lee 2021

2623

Adjusted HR: 0.93 (0.82–1.06)

Very low

Table 11Systolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of systolic blood pressure on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes
OR>1 indicates risk factor of progression to proliferative diabetic retinopathy
Systolic blood pressure Increasing systolic blood pressure
WESDR Klein 1994	996	Adjusted OR: 1.01 (0.99–1.03)	Very low
Systolic blood pressure >160mmHg
Janghorbani 2000	1349	Adjusted RR: 1.61 (1.18–2.20)	Very low
Systolic blood pressure Per 10 mmHg
WESDR Klein 1994	25	Adjusted HR: 1.14 (1.04–1.25)	Very low
Systolic blood pressure Per 10 mmHg
Grauslund 2009a	527	Adjusted OR: 0.91 (0.69–1.20)	Very low

Table 12Total cholesterol -Studies undertaking multivariable regression analyses to determine the effect of total cholesterol on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes
OR>1 indicates risk factor of progression to proliferative diabetic retinopathy
Total cholesterol ≥4.8 vs <4.8 mM
Lee 2021	2623	Adjusted HR: 0.93 (0.81–1.07)	Very low
Total cholesterol increases Per one SD
Nelson 1989	953	Adjusted RR: 1.80 (1.2–2.7)	Very low

Table 13Triglycerides -Studies undertaking multivariable regression analyses to determine the effect of triglycerides on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes
OR>1 indicates risk factor of progression to proliferative diabetic retinopathy
With increasing triglyceride level
Skrivarhaug 2006	368	Adjusted RR: 1.55 1.06–1.95	Low
Type 2 diabetes
Per one SD
Lee 2021	2623	Adjusted HR: 1.01 (0.91–1.12)	Low

Table 14Estimated glomerular filtration rate (eGFR) -Studies undertaking multivariable regression analyses to determine the effect of eGFR on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes HR >1 indicates risk factor of progression to proliferative diabetic retinopathy
a reduction in eGFR of >20%
Cho 2019	405	Adjusted HR: 2.55 (1.22–5.35)	Moderate
(eGFR) 46–60mL/min/1.73m2
Hsieh 2018	2096	Adjusted HR: 1.55(0.63–3.82)	Moderate
(eGFR) 30–45mL/min/1.73m2
Hsieh 2018	2096	Adjusted HR: 2.05 (0.72–5.86)	Moderate
(eGFR) <30 mL/min/1.73m2
Hsieh 2018	2096	Adjusted HR: 4.22 (1.27–14.07⁾	Moderate

Table 15Diabetic retinopathy severity at baseline -Studies undertaking multivariable regression analyses to determine the effect of diabetic retinopathy severity at baseline on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy
Lloyd 1995	322	Adjusted RR: 5.99 (3.03–11.9)	Moderate
Worsening baseline severity
Porta 2001	2013	Adjusted OR: 10.1 (5.9–17.2)	Moderate
WESDR	996	Adjusted OR: 1.38 (1.29–1.48)	Moderate
Type 2 diabetes
Mild NPDR
Lee 2021	2623	Adjusted HR: 13.58 (6.07–30.39)	Moderate
Moderate NPDR
Lee 2021	2623	Adjusted HR: 23.09 (10.68–49.91)	Moderate
Severe NPDR
Lee 2021	2623	Adjusted HR: 55.24 (25.54–119.46)	Moderate
Type 1 and type 2 diabetes
Very mild NPDR
Lee 2021	2623	Adjusted HR: 4.02 (3.25–4.96)	Moderate
mild NPDR
Lee 2021	2623	Adjusted HR: 6.71 (5.46–8.24)	Moderate
Moderate NPDR
Lee 2021	2623	Adjusted HR: 14.80 (12.10–18.09)	Moderate
Severe NPDR
Lee 2021	2623	Adjusted HR: 28.19 (22.92–34.67)	Moderate
Very severe NPDR
Lee 2021	2623	Adjusted HR: 58.42 (46.95–72.70)	Moderate

Table 16Diabetic retinopathy features at baseline -Studies undertaking multivariable regression analyses to determine the effect of diabetic retinopathy features at baseline on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 and 2 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy
IRMA Intraretinal microvascular abnormalities vs. venous beading in four quadrants
Lee 2017a	2823	Adjusted HR: 1.77 (1.25–2.49)	Very low
Dot/blot haemorrhages vs venous beading in four quadrants
Lee 2017a	2823	Adjusted HR: 1.47 (0.94–2.31)	Very low
Difference in number of microaneurysms at baseline and follow-up
WESDR Klein 1995	236	Adjusted HR: 1.04(1.02–1.07)	Very low
Ratio between number of microaneurysms at baseline and follow-up
WESDR Klein 1995	236	Adjusted HR: 1.05 (1.01–1.09)	Very low
Difference of ≥16 microaneurysms at baseline and follow-up
WESDR Klein 1995	236	Adjusted HR: 5.77 (2.24–14.89)	Very low

Table 17Body mass index (BMI) -Studies undertaking multivariable regression analyses to determine the effect of BMI on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy
BMI - per increase 1 kg/m2
Grauslund 2009a	573	Adjusted OR: 1.01 (0.86–1.20.9)	Very low
BMI per increase 4 kg/m2
WESDR Report XXII	996	Adjusted HR: 1.21 (1.07–1.36)	Very low
Type 2 diabetes
BMI = obesity at baseline (men:>31.0 kg/m2; women: >32.2 kg/ m2
WESDR Report XXII	1370	Adjusted RR: 1.41 (0.76–2.62)	Very low
BMI ≥34 vs. < 34 kg/m2
Nelson 1989	953	Adjusted RR: 1.0 (0.6–1.6)	Very low
Change in BMI during follow-up
Kim 1998	56	Adjusted RR: 1.33 (0.87–1.50)	Very low
BMI per one SD
Lee 2021	2623	Adjusted HR: 0.91 (0.79–1.03)	Very low

Table 18Smoking -Studies undertaking multivariable regression analyses to determine the effect of smoking on progression to PDR

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 1 diabetes OR >1 indicates risk factor of progression to proliferative diabetic retinopathy
Smoking Ever vs. never
WESDR Moss 1996	799	Adjusted OR: 1.15 (0.6–2.2)	Very low
Current smoker
WESDR Moss 1996	799	Adjusted OR: 0.86 (0.54–1.36)	Very low
Ex-smoker
WESDR Moss 1996	799	Adjusted OR: 0.94 (0.51–1.75)	Very low
Current smoker
Grauslund 2009a (Thorlund)	573	Adjusted OR: 1.9 (0.88–4.11)	Very low
Ex-smoker
Grauslund 2009a (Thorlund)	573	Adjusted OR: 0.87 (0.28–2.67)	Very low
Diabetic pack years smoked per 10 years
WESDR	996	Adjusted OR: 0.79 (0.66–0.95)	Very low
Type 2 diabetes
% Smokers vs. non-smokers
Gui 2013	205	Adjusted OR: 1.07 (1.04–1.11)	Very low
Smoking: yes vs. no
Nelson 1989	953	Adjusted RR: 0.70 (0.2–1.9)	Very low
Smoking: Ever vs. never
WESDR Moss 1991	1370	Adjusted OR: 1.13 (0.45–7.83)	Very low
Smoking
Gange 2021	71817	Adjusted OR: 0.84 (0.7–1.0)	Very low
Insulin Ex-smoker
WESDR Moss 1996	1370	Adjusted OR: 1.04 (0.49–2.22)	Very low
Insulin Current smoker
WESDR Moss 1996	1370	Adjusted OR: 1.15 (0.47–2.8)	Very low
Non-insulin Ex-smoker
WESDR Moss 1996	1370	Adjusted OR: 0.8 (0.23–2.8)	Very low
Non-insulin Current smoker
WESDR Moss 1996	1370	Adjusted OR: 0.25 (0.03–2.06)	Very low

Table 19Gender - Studies undertaking multivariable regression analyses to determine the effect of gender on progression to macular oedema

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes (Male vs female)
OR >1 indicates risk factor of progression to DMO at 2 years
1 (Lobo, 2018)	205	Adjusted OR: 4.09 (1.06–15.79)	Moderate

Table 20HbA1c -Studies undertaking multivariable regression analyses to determine the effect of HbA1c on progression to macular oedema

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes OR >1 indicates risk factor of progression to DMO
HbA1c>8%
Hammes, 2015	64784	Adjusted OR: 1,57 (1.288 1.903)	Low
HbA1c at 2 years follow up
Lobo 2018	205	Adjusted OR: 0.56 (0.35–0.90)	Moderate

Table 21Diastolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of diastolic blood pressure on progression to macular oedema

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes- Diastolic blood pressure

OR >1 indicates risk factor of progression to DMO

Lobo 2018

205

Adjusted OR: 1.03 (0.95–1.12)

Moderate

Table 22Systolic blood pressure -Studies undertaking multivariable regression analyses to determine the effect of systolic blood pressure on progression to macular oedema

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes

Systolic blood pressure

OR >1 indicates risk factor of progression to DMO

Lobo 2018

207

Adjusted OR: 0.96 (0.92–1.01)

Moderate

Table 23Total cholesterol -Studies undertaking multivariable regression analyses to determine the effect of total cholesterol on progression to macular oedema

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes

Total cholesterol, mmol/L

OR >1 indicates risk factor of progression to DMO

Lobo 2018

205

Adjusted OR: 0.98 (0.95–1.01)

Moderate

Table 24Triglycerides -Studies undertaking multivariable regression analyses to determine the effect of triglycerides on progression to macular oedema

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes

Triglycerides

OR >1 indicates risk factor of progression to DMO

Lobo 2018

205

Adjusted OR: (1.00 1.00–1.01)

Low

Table 25Estimated glomerular filtration rate (eGFR) -Studies undertaking multivariable regression analyses to determine the effect of eGFR on progression to macular oedema

No. of studies	Sample size	Effect size (95%CI)	Quality
Type 2 diabetes HR >1 indicates risk factor of progression to DMO
61–90 eGFR, mL/min/1.73m2
Hsieh 2018	1055	Adjusted HR: 1.226 (0.711–2.115)	Low
46–60 eGFR, mL/min/1.73m2
Hsieh 2018	418	Adjusted HR: 1.218 (0.559–2.654)	Low
30–45 eGFR, mL/min/1.73m2
Hsieh 2018	248	Adjusted HR: 3.106 (1.268–7.609)	Low
<30 eGFR, mL/min/1.73m2
Hsieh 2018	98	Adjusted HR: 1.849 (0.568–6.025)	Low

Table 26Hypertension-Studies undertaking multivariable regression analyses to determine the effect of hypertension o on progression to macular oedema

No. of studies

Sample size

Effect size (95%CI)

Quality

Type 2 diabetes

Hypotension (>140/80 mmHg)

OR >1 indicates risk factor of hypertension on progression to macular oedema.

1 (Hammes, 2015)

64784

Adjusted OR: 1.39 (1.11–1.74)

Low

Study	Reason for exclusion
Agarwal, M., Sachdeva, M., Shah, S. et al (2022) Correlating the patterns of diabetic macular edema, optical coherence tomography biomarkers and grade of diabetic retinopathy with stage of renal disease. International Ophthalmology 42(11): 3333–3343 [PubMed: 35633427]	- measuring progression to PDR
Allen, D.W., Liew, G., Cho, Y.H. et al (2022) Thirty-Year Time Trends in Diabetic Retinopathy and Macular Edema in Youth With Type 1 Diabetes. Diabetes Care 45(10): 2247–2254 [PubMed: 35594057]	- Prevalence study
Arulanandham, A., Raju, A., Pradeep Rajkumar, L.A. et al (2012) Prevalence of clinically significant macular edema [CSME] among glitazone users and non- users of type-2 DM patients with diabetic retinopathy. International Journal of Drug Development and Research 4(2): 132–137	- Prevalence study
Bailey, C C, Sparrow, J M, Grey, R H et al (1999) The National Diabetic Retinopathy Laser Treatment Audit. III. Clinical outcomes. Eye (London, England) 13 (Pt 2): 151–9 [PubMed: 10450373]	- End point measuring progression to PDR
Bertelsen, Geir, Peto, Tunde, Lindekleiv, Haakon et al (2013) Tromso eye study: prevalence and risk factors of diabetic retinopathy. Acta ophthalmologica 91(8): 716–21 [PubMed: 22994366]	- End point measuring progression to PDR
Burgess, P.I., MacCormick, I.J. C., Harding, S.P. et al (2013) Epidemiology of diabetic retinopathy and maculopathy in Africa: A systematic review. Diabetic Medicine 30(4): 399–412 [PMC free article: PMC4463765] [PubMed: 22817387]	- a systematic review used to crosscheck studies
Burnett, Anthea, Lee, Ling, D'Esposito, Fabrizio et al (2019) Rapid assessment of avoidable blindness and diabetic retinopathy in people aged 50 years and older in the National Capital District of Papua New Guinea. The British journal of ophthalmology 103(6): 743–747 [PubMed: 29973367]	- End point measuring progression to PDR
Busch, C., Katzmann, J.L., Jochmann, C. et al (2021) General health of patients with diabetic macular edema-The LIPSIA study. PLoS ONE 16(6june2021): e0252321 [PMC free article: PMC8195383] [PubMed: 34115786]	wrong study design: narrative review
Chung, Yoo-Ri, Park, Sung Wook, Choi, Shin-Young et al (2017) Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovascular diabetology 16(1): 4 [PMC free article: PMC5219811] [PubMed: 28061854]	none of the prognostic factors reported match review.
Creuzot-Garcher, C., Massin, P., Srour, M. et al (2022) Epidemiology of Treated Diabetes Ocular Complications in France 2008–2018-The LANDSCAPE French Nationwide Study. Pharmaceutics 14(11): 2330 [PMC free article: PMC9697089] [PubMed: 36365148]	- Narrative review
Crosby-Nwaobi, Roxanne, Chatziralli, Irini, Sergentanis, Theodoros et al (2015) Cross Talk between Lipid Metabolism and Inflammatory Markers in Patients with Diabetic Retinopathy. Journal of diabetes research 2015: 191382 [PMC free article: PMC4532932] [PubMed: 26295054]	- End point measuring progression to PDR
Das, Anthony Vipin, Prashanthi, Gumpili Sai, Das, Taraprasad et al (2021) Clinical profile and magnitude of diabetic retinopathy: An electronic medical record-driven big data analytics from an eye care network in India. Indian journal of ophthalmology 69(11): 3110–3117 [PMC free article: PMC8725066] [PubMed: 34708751]	- End point measuring progression to PDR
Das, Radha, Kerr, Rebecca, Chakravarthy, Usha et al (2015) Dyslipidemia and Diabetic Macular Edema: A Systematic Review and Meta-Analysis. Ophthalmology 122(9): 1820–7 [PubMed: 26150053]	- none of the prognostic factors reported match review protocol
Fairchild, J M, Hing, S J, Donaghue, K C et al (1994) Prevalence and risk factors for retinopathy in adolescents with type 1 diabetes. The Medical journal of Australia 160(12): 757–62 [PubMed: 8208191]	- measuring prevalence of PDR
Henricsson, M, Sellman, A, Tyrberg, M et al (1999) Progression to proliferative retinopathy and macular oedema requiring treatment. Assessment of the alternative classification of the Wisconsin Study. Acta ophthalmologica Scandinavica 77(2): 218–23 [PubMed: 10321543]	- mixed population of PDR and DMO
Hirai, Flavio E, Knudtson, Michael D, Klein, Barbara E K et al (2008) Clinically significant macular edema and survival in type 1 and type 2 diabetes. American journal of ophthalmology 145(4): 700–6 [PMC free article: PMC2440953] [PubMed: 18226797]	- measuring progression to PDR
Jones, Colin D, Greenwood, Richard H, Misra, Aseema et al (2012) Incidence and progression of diabetic retinopathy during 17 years of a population-based screening program in England. Diabetes care 35(3): 592–6 [PMC free article: PMC3322726] [PubMed: 22279031]	- Mixed population
Kaba, Q., Tai, F., Al-Awadi, A. et al (2022) Examining the Relationship Between Diabetic Macular Edema, and Obstructive Sleep Apnea. Clinical Ophthalmology 16: 1215–1223 [PMC free article: PMC9037844] [PubMed: 35480621]	Association study
Klein, R, Klein, B E, Moss, S E et al (1994) Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Archives of internal medicine 154(19): 2169–78 [PubMed: 7944837]	- End point measuring progression to PDR
Klein, R, Klein, B E, Moss, S E et al (1994) The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Archives of ophthalmology (Chicago, Ill.: 1960) 112(9): 1217–28 [PubMed: 7619101]	- End point measuring progression to PDR
Leese, G. (2004) Longitudinal study examining the risk factors for proliferative retinopathy and maculopathy in type-I diabetes: The Royal College of Physicians of Edinburgh Diabetes Register Group. Eye 18(8): 814–820 [PubMed: 14752505]	Cross sectional study
Leong, W.B., Jadhakhan, F., Taheri, S. et al (2016) Effect of obstructive sleep apnoea on diabetic retinopathy and maculopathy: A systematic review and meta-analysis. Diabetic Medicine 33(2): 158–168 [PubMed: 26031931]	- a systematic review used to check for primary studies
Li, Z., Liu, R., Xiao, O. et al (2019) Progression of myopic maculopathy in highly myopic chinese eyes. Investigative Ophthalmology and Visual Science 60(4): 1096–1104 [PubMed: 30901386]	- wrong population
Lim, Laurence Shen, Tai, E Shyong, Mitchell, Paul et al (2010) C-reactive protein, body mass index, and diabetic retinopathy. Investigative ophthalmology & visual science 51(9): 4458–63 [PubMed: 20805569]	Cross sectional study
Lloyd, C E, Klein, R, Maser, R E et al (1995) The progression of retinopathy over 2 years: the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. Journal of diabetes and its complications 9(3): 140–8 [PubMed: 7548977]	- End point measuring progression to PDR
Lobo, C., Santos, T., Marques, I.P. et al (2022) Characterisation of progression of macular oedema in the initial stages of diabetic retinopathy: a 3-year longitudinal study. Eye (Basingstoke) [PMC free article: PMC9873671] [PubMed: 35066579]	- end point not measuring prognostic factors
Marques, I.P., Ribeiro, M.L., Santos, T.P. et al (2022) Different Risk Profiles for Progression of Nonproliferative Diabetic Retinopathy: A 2-Year Study. Ophthalmology and Therapy [PMC free article: PMC9834451] [PubMed: 36495395]	- End point measuring progression to PDR
Martin-Merino, E, Fortuny, J, Rivero-Ferrer, E et al (2017) Risk factors for diabetic macular oedema in type 2 diabetes: A case-control study in a United Kingdom primary care setting. Primary care diabetes 11(3): 288–296 [PubMed: 28395937]	- no multivariate analysis conducted
Moss, S E; Klein, R; Klein, B E (1994) Ocular factors in the incidence and progression of diabetic retinopathy. Ophthalmology 101(1): 77–83 [PubMed: 8302567]	- End point measuring progression to PDR
Moss, S E; Klein, R; Klein, B E (1994) Ten-year incidence of visual loss in a diabetic population. Ophthalmology 101(6): 1061–70 [PubMed: 8008348]	- End point do not match that specified in the protocol
Nguyen, H T, Luzio, S D, Dolben, J et al (1996) Dominant risk factors for retinopathy at clinical diagnosis in patients with type II diabetes mellitus. Journal of diabetes and its complications 10(4): 211–9 [PubMed: 8835921]	- End point measuring progression to PDR
Panozzo, G., Mura, G.D., Franzolin, E. et al (2022) Early DMO: a predictor of poor outcomes following cataract surgery in diabetic patients. The DICAT-II study. Eye (Basingstoke) 36(8): 1687–1693 [PMC free article: PMC8330474] [PubMed: 34345028]	- End point do not match that specified in the protocol
Pires, Isabel, Santos, Ana Rita, Nunes, Sandrina et al (2013) Subclinical macular edema as a predictor of progression to clinically significant macular edema in type 2 diabetes. Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde 230(4): 201–6 [PubMed: 24080704]	- prognostic factor does not match review protocol
Radwan, Salma H, Soliman, Ahmed Z, Tokarev, Julian et al (2015) Association of Disorganization of Retinal Inner Layers With Vision After Resolution of Center-Involved Diabetic Macular Edema. JAMA ophthalmology 133(7): 820–5 [PubMed: 25950417]	- End point measuring progression to PDR
Rajalakshmi, Ramachandran, Amutha, Anandakumar, Ranjani, Harish et al (2014) Prevalence and risk factors for diabetic retinopathy in Asian Indians with young onset type 1 and type 2 diabetes. Journal of diabetes and its complications 28(3): 291–7 [PubMed: 24512748]	- End point measuring progression to PDR
Raum, Philipp, Lamparter, Julia, Ponto, Katharina A et al (2015) Prevalence and Cardiovascular Associations of Diabetic Retinopathy and Maculopathy: Results from the Gutenberg Health Study. PloS one 10(6): e0127188 [PMC free article: PMC4468098] [PubMed: 26075604]	- End point measuring progression to PDR
Schreur, Vivian, van Asten, Freekje, Ng, Heijan et al (2018) Risk factors for development and progression of diabetic retinopathy in Dutch patients with type 1 diabetes mellitus. Acta ophthalmologica 96(5): 459–464 [PMC free article: PMC6174939] [PubMed: 30188024]	- End point measuring progression to PDR
Shah, S P, Patel, M, Thomas, D et al (2006) Factors predicting outcome of vitrectomy for diabetic macular oedema: results of a prospective study. The British journal of ophthalmology 90(1): 33–6 [PMC free article: PMC1856901] [PubMed: 16361663]	- population does not match protocol
Shalchi, Zaid, Okada, Mali, Bruynseels, Alice et al (2018) Effect of glycosylated hemoglobin on response to ranibizumab therapy in diabetic macular edema: real-world outcomes in 312 patients. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 53(4): 415–419 [PubMed: 30119798]	- wrong intervention
Singh, Harsh V, Das, Shubhra, Deka, Dipali C et al (2021) Prevalence of diabetic retinopathy in self-reported diabetics among various ethnic groups and associated risk factors in North-East India: A hospital-based study. Indian journal of ophthalmology 69(11): 3132–3137 [PMC free article: PMC8725127] [PubMed: 34708755]	- prevalence
Sun, Jennifer K, Lin, Michael M, Lammer, Jan et al (2014) Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA ophthalmology 132(11): 1309–16 [PubMed: 25058813]	wrong intervention/ outcome measurement
Sun, Zihan, Tang, Fangyao, Wong, Raymond et al (2019) OCT Angiography Metrics Predict Progression of Diabetic Retinopathy and Development of Diabetic Macular Edema: A Prospective Study. Ophthalmology 126(12): 1675–1684 [PubMed: 31358386]	- outcome/End point do not match that specified in the protocol Mixed population
Syriga, Maria, Ioannou, Zina, Pitsas, Christos et al (2022) Diabetic retinopathy in Greece: prevalence and risk factors studied in the medical retina clinic of a Greek tertiary hospital. International ophthalmology 42(6): 1679–1687 [PubMed: 35098418]	- End point do not match that specified in the protocol Prevalence study
Terada, Noriko, Murakami, Tomoaki, Uji, Akihito et al (2020) Hyperreflective Walls in Foveal Cystoid Spaces as a Biomarker of Diabetic Macular Edema Refractory to Anti-VEGF Treatment. Scientific reports 10(1): 7299 [PMC free article: PMC7190628] [PubMed: 32350366]	- End point do not match that specified in the protocol Wrong intervention/ outcome measure
Vujosevic, Stela, Pucci, Porzia, Casciano, Margherita et al (2017) A decade-long telemedicine screening program for diabetic retinopathy in the north-east of Italy. Journal of diabetes and its complications 31(8): 1348–1353 [PubMed: 28551296]	- End point do not match that specified in the protocol Wrong population
Wang, Yu T, Tadarati, Mongkol, Wolfson, Yulia et al (2016) Comparison of Prevalence of Diabetic Macular Edema Based on Monocular Fundus Photography vs Optical Coherence Tomography. JAMA ophthalmology 134(2): 222–8 [PubMed: 26719967]	- End point do not match that specified in the protocol Wrong outcome measurement
Wang, Yu, Lin, Zhong, Zhai, Gang et al (2022) Prevalence of and Risk Factors for Diabetic Retinopathy and Diabetic Macular Edema in Patients with Early- and Late-Onset Diabetes Mellitus. Ophthalmic research 65(3): 293–299 [PMC free article: PMC9227665] [PubMed: 32353847]	- End point do not match that specified in the protocol Mixed population
Zander, E, Herfurth, S, Bohl, B et al (2000) Maculopathy in patients with diabetes mellitus type 1 and type 2: associations with risk factors. The British journal of ophthalmology 84(8): 871–6 [PMC free article: PMC1723591] [PubMed: 10906094]	Cross sectional study
Zhang, Jun, Ma, Jingxue, Zhou, Nalei et al (2015) Insulin use and risk of diabetic macular edema in diabetes mellitus: a systemic review and meta-analysis of observational studies. Medical science monitor: international medical journal of experimental and clinical research 21: 929–36 [PMC free article: PMC4384512] [PubMed: 25816765]	- End point do not match that specified in the protocol Systematic review used to check for primary studies
Zhu, Z., Cheng, W., Bulloch, G. et al (2022) Choriocapillaris flow deficit as a biomarker for diabetic retinopathy and diabetic macular edema: 3-year longitudinal cohort: Choriocapillaris flow predicts DR progression and DME development. American journal of ophthalmology [PubMed: 36436548]	- End point do not match that specified in the protocol Prognostic factor not included in review protocol
Zhuang, Xuenan, Cao, Dan, Yang, Dawei et al (2019) Association of diabetic retinopathy and diabetic macular oedema with renal function in southern Chinese patients with type 2 diabetes mellitus: a single-centre observational study. BMJ open 9(9): e031194 [PMC free article: PMC6731866] [PubMed: 31494622]	Cross sectional study

Title	Reason for exclusion
Olson, J, Sharp, P, Goatman, K et al (2013) Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema: a prospective, multicentre, UK study. Health technology assessment (Winchester, England) 17(51): 1–142 [PMC free article: PMC4781285] [PubMed: 24225334]	Not applicable - not comparing prognostic factors