Risk factors for long-term diabetic retinopathy in type 1 diabetes: evaluation of evidence from the Vascular Diabetic Complications in Southeast Sweden study

Diabetic retinopathy (DR) is by far the most common long-term complication in diabetes, and it is estimated that 95–97% of patients with type 1 diabetes will be affected in time (1,2). Given that blindness is expected to affect 3–8% of type 1 diabetes patients (3,4), it is vital to perform eye screening in order to treat sight-threatening complications prior to irreversible visual loss (5,6).

While ocular treatment of DR by laser photocoagulation, intravitreal therapy and vitrectomy is only indicated at the advanced stages of proliferative DR (PDR) (7) and diabetic macular edema (8,9), early prevention or arrest of DR has been tested systemically and topically with mixed results. Potential targets for preventive oral treatment have been general blood pressure lowering (10,11), inhibition of the renin-angiotensin system (12-14), and lipid lowering with fenofibrate (11,15). Likewise, topically neuroprotection has been tested with limited short-term effects (16).

So far, strict glycemic control has constantly been confirmed as the most important preventer of DR. This was first demonstrated in the Diabetes Control and Complication Trial (DCCT), which was a 6.5 years randomized trial of patients with type 1 diabetes aimed to evaluate the effect of strict glycemic control with incident and progressive DR as principal endpoints (17). In brief, DR did not differ between groups for the first two or three years, but afterwards a stunning reduction of 75% and 54% for incident and progressive DR, respectively, was demonstrated in the strict glycemic control group. Similar results were confirmed for patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) (18). In this study, patients randomized to strict glycemic control had a 21% lower 12-year risk of a 2-step DR progression.

For practical reasons, hemoglobin A1c (HbA1c) is used to indicate glycemic control. However, HbA1c only reflects blood sugar levels within the last three months. Therefore, it is vulnerable to differences in glycemic control over time (19). A potential approach to account for this was presented in the Vascular Diabetic Complications in Southeast Sweden (VISS) study, in which the term long-term mean weighted HbA1c (wHbA1c) was introduced (20). In brief, the VISS study was a population-based observational study of 451 patients diagnosed with diabetes prior to the age of 35 between 1983 and 1987. Patients were followed for 18–24 years and level of DR has been determined by fundus photography and evaluated in association with wHbA1c.

Interestingly, lower wHbA1c was the only independent predictor of long-term PDR. Weighted HbA1c was also highly predictive of incident DR illustrated by the fact that 20 of 36 patients with wHbA1c ≤ 50 mmol/mol (6.7%) did not have DR at follow-up as opposed to none of 49 patients with wHbA1c > 80 mmol/mol (9.5%).

In addition to weighted glycemic control, onset of diabetes prior to the age of 6 years also associated with longer duration before development of DR. In contrast to the present study, a 25-year follow up of 995 patients with type 1 diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy did not identify young age at onset (defined as age 0–9 years) as a predictor of progression of DR, incident PDR, or 2-step or more improvement in DR, respectively (21). While it is well known that PDR is extremely seldom in children (22), the concept of young age at onset as a protective factor for long-term DR is an interesting finding that warrants further investigation.

The VISS study strengthens the evidence identifying glycemic control as the most important modifiable risk factor of DR. Patients with diabetes and treating physicians should be aware of the essential potential to prevent or delay DR by optimizing glycemic control. In addition, life-long diabetic eye screening should be encouraged to prevent vision loss and blindness in diabetes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes.2019.11.01). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Grauslund J, Green A, Sjolie AK. Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients. Diabetologia 2009;52:1829-35. [Crossref] [PubMed]
2. Broe R, Rasmussen ML, Frydkjaer-Olsen U, et al. The 16-year incidence, progression and regression of diabetic retinopathy in a young population-based Danish cohort with type 1 diabetes mellitus: The Danish cohort of pediatric diabetes 1987 (DCPD1987). Acta Diabetol 2014;51:413-20. [Crossref] [PubMed]
3. Klein R, Lee KE, Gangnon RE, et al. The 25-year incidence of visual impairment in type 1 diabetes mellitus the wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology 2010;117:63-70. [Crossref] [PubMed]
4. Grauslund J, Green A, Sjolie AK. Blindness in a 25-year follow-up of a population-based cohort of Danish type 1 diabetic patients. Ophthalmology 2009;116:2170-4. [Crossref] [PubMed]
5. Grauslund J, Andersen N, Andresen J, et al. Evidence-based Danish guidelines for screening of diabetic retinopathy. Acta Ophthalmol 2018;96:763-9. [Crossref] [PubMed]
6. Scanlon PH. The English National Screening Programme for diabetic retinopathy 2003-2016. Acta Diabetol 2017;54:515-25. [Crossref] [PubMed]
7. DRS. Preliminary report on effects of photocoagulation therapy. The Diabetic Retinopathy Study Research Group. Am J Ophthalmol 1976;81:383-96. [Crossref] [PubMed]
8. ETDRS. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Archives of Ophthalmology 1985;103:1796-806. [Crossref] [PubMed]
9. Diabetic Retinopathy Clinical Research N. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372:1193-203. [Crossref] [PubMed]
10. UKPDS. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. [Crossref] [PubMed]
11. Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. New England Journal of Medicine 2010;363:233-44. [Crossref] [PubMed]
12. Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008;372:1394-402. [Crossref] [PubMed]
13. Sjolie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008;372:1385-93. [Crossref] [PubMed]
14. Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998;351:28-31. [Crossref] [PubMed]
15. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97. [Crossref] [PubMed]
16. Simó R, Hernandez C, Porta M, et al. Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial. Diabetes 2019;68:457-63. [Crossref] [PubMed]
17. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. [Crossref] [PubMed]
18. . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53. [Crossref] [PubMed]
19. Jørgensen TM, Grauslund J, Sjolie AK, et al. Major diabetes-related vascular events do not improve glycaemic control in a population-based cohort of type 1 diabetic individuals. Scand J Clin Lab Invest 2009;69:748-51. [Crossref] [PubMed]
20. Nordwall M, Fredriksson M, Ludvigsson J, et al. Impact of Age of Onset, Puberty, and Glycemic Control Followed From Diagnosis on Incidence of Retinopathy in Type 1 Diabetes: The VISS Study. Diabetes Care 2019;42:609-16. [Crossref] [PubMed]
21. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 2008;115:1859-68. [Crossref] [PubMed]
22. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984;102:520-6. [Crossref] [PubMed]