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 Table of Contents  
Year : 2023  |  Volume : 2  |  Issue : 1  |  Page : 1-3

Glucose control and diabetic retinopathy: Is there more than meets the eye?

1 Department of Ophthalmology, Chellaram Diabetes Institute, Pune, Maharashtra, India
2 Department of Endocrinology, Lisie Hospital, Kochi, Kerala, India

Date of Submission16-Nov-2022
Date of Decision15-Dec-2022
Date of Acceptance15-Dec-2022
Date of Web Publication18-Jan-2023

Correspondence Address:
Savita Bhat
Chellaram Diabetes Institute, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_CDRP_22_22

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How to cite this article:
Bhat S, Menon AS. Glucose control and diabetic retinopathy: Is there more than meets the eye?. Chron Diabetes Res Pract 2023;2:1-3

How to cite this URL:
Bhat S, Menon AS. Glucose control and diabetic retinopathy: Is there more than meets the eye?. Chron Diabetes Res Pract [serial online] 2023 [cited 2023 Jun 2];2:1-3. Available from: https://cdrpj.org//text.asp?2023/2/1/1/368027

  Introduction Top

Diabetic retinopathy (DR) is a leading cause of preventable blindness in the world.[1] It is well known that there is an important need to prevent and treat DR in India, which has a large burden of people with diabetes.[2] Hyperglycemia is strongly associated with DR. Landmark studies such as the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have shown that intensive glucose control, along with blood pressure control, is associated with reductions in the onset and progression of DR.[3],[4] Nevertheless, it is important to understand that there are some nuances which are important in understanding the link between glucose control and DR, and this will form the basis of this article.

  Relationship between Rapid Tightening of Glucose Control and Worsening of Retinopathy Top

It is well known that there is a temporary worsening of DR after intensive glucose control in type 2 diabetes,[5] and in type 1 diabetes as well.[6] People with retinopathy at baseline seem to be particularly susceptible to a worsening of retinopathy; other risk factors for such early worsening of retinopathy include longer duration of diabetes, the larger amplitude of hemoglobin A1C (HbA1c) reduction, the extent of severity of baseline retinopathy, and duration of uncontrolled hyperglycemia. The mechanisms for such early worsening of DR continue to be debated. It has been postulated that both good glucose control and insulin therapy may increase the production of insulin-like grown factor-1 (IGF-1) and that IGF-1 in turn increases the expression of various growth factors particularly vascular endothelial growth factor (VEGF) – which is a key factor in the pathogenesis of retinopathy. VEGF leads to the worsening of retinopathy through new vessel formation and blood vessel leakage. These problems might be more severe in people with underlying retinopathy because studies have shown that improved glucose control in the presence of preexisting retinal hypoxia and retinopathy may impart a higher vulnerability to worsening of retinopathy.[6] Recent studies have identified this early worsening as a transient problem, and it has been suggested that fundus abnormalities would disappear by 18 months, and eventually, long-term glucose control is beneficial for the preventing worsening of retinopathy.[4] Taken together these studies continue to endorse the view that glucose control is beneficial; caution, however, may be warranted before embarking on intensive glucose control therapy in subjects with very high glucose levels, with long duration of uncontrolled hyperglycemia, and who also have severe DR at baseline. In such patients, a more gradual return to normoglycemia, bringing HbA1c to below 7% over 6 months or more may be appropriate-though therapy has to be individualized.

  Glycemic Variability and Retinopathy Top

It is well known that glycemic variability is associated with DR. This has come to be of importance with the concept of TIR (percentage time spent with glucose levels between 70 and 180 mg/dl) with continuous glucose monitoring. The time in range is said to be an index of glycemic variability because if a smaller proportion of time is spent in range, then that must mean that the time above/below range must be larger, and by implication, a lower time in range points to greater glycemic variability. In a recent international study, it has been shown that a decrease in the time in range was associated with an increase in DR.[7] In a recent case–control study from India, indices of glycemic variability, including time in range, were numerically worse in people with type 2 diabetes with retinopathy as compared with people with type 2 diabetes and no retinopathy, though these differences were not statistically significant.[8] This study also showed that a lower proportion of elderly subjects (>65 years) with DR could maintain time below range targets compared with those with diabetes and no DR (P < 0.05), suggesting that this population is particularly prone to hypoglycemias. Clearly, given the complex association between glucose control and retinopathy, and given the possibility of early worsening of retinopathy with very intensive control, more evidence needs to be built around the concept of glycemic variability and the impact of treating it, especially with regard to DR outcomes. Therefore, achieving target glucose levels could be a priority for preventing the onset/progression of DR, rather than addressing the glycemic variability through intensive control.

  Agents Reducing Blood Glucose Levels and Retinopathy Top

It is well known that older antidiabetic agents such as sulfonylureas, metformin, and insulin have been used in the landmark trials such as the UKPDS[4] and DCCT,[3] and the analysis of these studies has shown that it is glucose control and probably not any one of the agents, that has a beneficial effect on DR. Having mentioned that it is instructive to look at other agents which have an impact on retinopathy. Thiazolidinediones such as pioglitazone have been linked to the occurrence of diabetic macular edema (DME). In a retrospective study of 103,368 patients and no macular edema at baseline, thiazolidinedione use was associated with a significantly increased risk of DME at 1-year and 10-year follow-ups, there being no difference between pioglitazone and rosiglitazone in this regard.[9] Spontaneous resolution of DME after stopping thiazolidinediones has also been reported.[10] However, the clinical benefits and risks of stopping thiazolidinediones in such settings have to be based on a discussion with the diabetes care management team, and in general, treatment of DME in such settings has to be based upon standard management guidelines including intravitreous injections and lasers as required. Glucagon-like peptide 1 (GLP-1) receptor agonists are increasingly used in diabetes management, given their cardiovascular benefits. In these cardiovascular outcome trials with GLP-1 receptor agonists (liraglutide/semaglutide/dulaglutide), rapid worsening of DR has been noted.[11] Hence, in patients with unstable or very severe retinopathy, it is better to consider alternative therapies or defer GLP-1 receptor agonist therapy till retinopathy has been stabilized. Hydroxychloroquine, an agent used for treating rheumatoid arthritis, has been shown to lower blood glucose levels.[12] It must be remembered that hydroxychloroquine may be associated with retinal toxicity and that people with diabetes are uniquely predisposed to DR. Retinal thinning on optical computerized tomography may be an early clue to a future occurrence of retinopathy in people taking hydroxychloroquine.[13] In people with rheumatoid arthritis and DR, it is best to discontinue hydroxychloroquine-though as always treatment should be individualized and after discussion with the patient and the treating physician and rheumatologist.

The use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in diabetes is known to provide cardiorenal benefits. It has been suggested that some of the mechanisms, such as inflammation, oxidative stress, vascular damage, retinal hypoxia, and edema associated with chronic hyperglycemia, might be beneficially tackled by the use of SGLT2i.[14] This group of agents could also reduce glial activation and VEGF expression, as shown in animal studies with tofogliflozin.[15] It has also been suggested that a low-grade ketosis-like state induced by SGLT2i could be beneficial for retinal fuel energetics and thus protect against DR.[16] A recent meta-analysis has suggested that in people with a shorter duration of diabetes of below 10 years, SGLT2i could protect against DR.[17] However, these remain inconclusive, and the effect of SGLT2i on DR needs to be established by comprehensive studies.

  Impact of Pregnancy on Retinopathy Top

Pregnancy has long been known to be associated with the progression of retinopathy without any long-term deleterious effects. The greatest risk of worsening occurs during the second trimester. One of the main factors implicated for such worsening is the rapid tightening of glucose control during early pregnancy. Duration of diabetes, the severity of retinopathy at conception, hyperglycemic control, anemia, and progression of coexisting hypertension also play a role. It is recommended that any retinopathy be stabilized before conception. Good diabetic control before and during pregnancy can help prevent this increase in the progression and serious vision loss but this has to be ideally planned before conception.[18],[19]

  Summary Top

While it is well known that in most patients, tight glucose control prevents the onset and progression of DR in the long term, there is emerging evidence that the connections between blood glucose and retinopathy are complex in certain circumstances. Appropriate guideline-directed screening for retinopathy onset and progression is important for therapy, which includes both direct ophthalmological intervention as well as systemic risk factor control. Both ophthalmologists and endocrinologists/diabetes specialists should keep in mind the aforementioned nuances in the hyperglycemia-retinopathy connections and the management of people with DR should essentially be multidisciplinary.

  References Top

Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond) 2015;2:17.  Back to cited text no. 1
Unnikrishnan AG, Kalra S, Tandon N. Diabetic retinopathy care in India: An endocrinology perspective. Indian J Endocrinol Metab 2016;20:S1-2.  Back to cited text no. 2
Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. 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.  Back to cited text no. 3
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.  Back to cited text no. 4
Arun CS, Pandit R, Taylor R. Long-term progression of retinopathy after initiation of insulin therapy in type 2 diabetes: An observational study. Diabetologia 2004;47:1380-4.  Back to cited text no. 5
Akil H, Burgess J, Nevitt S, Harding SP, Alam U, Burgess P. Early worsening of retinopathy in type 1 and type 2 diabetes after rapid improvement in glycaemic control: A systematic review. Diabetes Ther 2022;13:1-23.  Back to cited text no. 6
Lu J, Ma X, Zhou J, Zhang L, Mo Y, Ying L, et al. Association of time in range, as assessed by continuous glucose monitoring, with diabetic retinopathy in Type 2 diabetes. Diabetes Care 2018;41:2370-6.  Back to cited text no. 7
Kulkarni AS, Kavitha KV, Sarkar NS, Purandare VB, Bhat S, Tiwari S, et al. Glycemic variability and other risk factors for diabetic retinopathy: A pilot case-control study. Chron Diabetes Res Pract 2022;1:13-7.  Back to cited text no. 8
  [Full text]  
Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med 2012;172:1005-11.  Back to cited text no. 9
Liazos E, Broadbent DM, Beare N, Kumar N. Spontaneous resolution of diabetic macular oedema after discontinuation of thiazolidenediones. Diabet Med 2008;25:860-2.  Back to cited text no. 10
Yoshida Y, Joshi P, Barri S, Wang J, Corder AL, O'Connell SS, et al. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes – A systematic review and meta-analysis. J Diabetes Complications 2022;36:108255.  Back to cited text no. 11
Pareek A, Chandurkar N, Thomas N, Viswanathan V, Deshpande A, Gupta OP, et al. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: A double blind, randomized comparison with pioglitazone. Curr Med Res Opin 2014;30:1257-66.  Back to cited text no. 12
Melles RB, Marmor MF. Rapid macular thinning is an early indicator of hydroxychloroquine retinal toxicity. Ophthalmology 2022;129:1004-13.  Back to cited text no. 13
Lahoti S, Nashawi M, Sheikh O, Massop D, Mir M, Chilton R. Sodium-glucose co-transporter 2 inhibitors and diabetic retinopathy: Insights into preservation of sight and looking beyond. Cardiovasc Endocrinol Metab 2021;10:3-13.  Back to cited text no. 14
Hanaguri J, Yokota H, Kushiyama A, Kushiyama S, Watanabe M, Yamagami S, et al. The effect of sodium-dependent glucose cotransporter 2 inhibitor tofogliflozin on neurovascular coupling in the retina in type 2 diabetic mice. Int J Mol Sci 2022;23:1362.  Back to cited text no. 15
Mudaliar S, Hupfeld C, Chao DL. SGLT2 inhibitor-induced low-grade ketonemia ameliorates retinal hypoxia in diabetic retinopathy – A novel hypothesis. J Clin Endocrinol Metab 2021;106:1235-44.  Back to cited text no. 16
Ma Y, Lin C, Cai X, Hu S, Zhu X, Lv F, et al. The association between the use of sodium glucose cotransporter 2 inhibitor and the risk of diabetic retinopathy and other eye disorders: A systematic review and meta-analysis. Expert Rev Clin Pharmacol 2022;15:877-86.  Back to cited text no. 17
Phelps RL, Sakol P, Metzger BE, Jampol LM, Freinkel N. Changes in diabetic retinopathy during pregnancy. Correlations with regulation of hyperglycemia. Arch Ophthalmol 1986;104:1806-10.  Back to cited text no. 18
Arun CS, Taylor R. Influence of pregnancy on long-term progression of retinopathy in patients with type 1 diabetes. Diabetologia 2008;51:1041-5.  Back to cited text no. 19


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