Optimizing Medical Management for Patients with Diabetes-Related Retinopathy

DR occurs exclusively with exposure to hyperglycemia. The degree of hyperglycemia and its duration are two major risk factors for the development of retinopathy. (Figure 1) (16). Therefore, the cornerstone of medical management is to prevent hyperglycemia.

Lowering A1C reduces the development and progression of DR (17–20). The more intensive the control of hyperglycemia is, the greater the benefits will be. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial showed a reduction in the development and progression of all stages of retinopathy in the intensive control group (mean A1C 6.4%) compared to the standard care group (mean A1C 7.5%), with the greatest effect noted in patients with mild retinopathy at baseline (17). Even a small decrease in A1C can be beneficial. Lowering A1C by 1 percentage point can reduce the risk of DR development by 35% and the risk of its progression by 15–25% (21). Intensive control has also been shown to have persistent benefits in both type 1 and type 2 diabetes (a so-called “legacy effect”) after the conclusion of study intervention, despite similar A1C values between the study and control groups at extended follow-up (22–24). These findings suggest that glycemic control has long-term benefits even if not consistently maintained over time (22–24).

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 recommend a personalized approach to setting target A1C levels for individual patients (25). An A1C <7% is considered an ideal target for many individuals; however, complications such as retinopathy can still occur at that level, so lowering the target should be considered in specific situations where either the risk of a complication is high (e.g., during pregnancy or in young adults) or the risk of treatment is very low (e.g., in patients treated with medications such as metformin that do not confer a risk of hypoglycemia). Similarly, it may be appropriate to increase the target to <8% in individuals who are at high risk of hypoglycemia (e.g., those with hypoglycemia unawareness or dementia) or in those for whom the risk of developing complications from diabetes is low (e.g., individuals with a limited life expectancy) (25).

The rapid correction of a long-standing elevation in A1C is associated with a transient worsening of retinopathy and DME (26–28), although the optimal rate at which A1C should be decreased is not clear. As illustrated in Figure 2, although there are similar rates of progression of DR in the short term after initiating intensive glycemic control, there is a significant reduction in progression in the long term (26,29,30). One large clinical trial did not find evidence that a slower rate of achieving targets was beneficial (28), but strong data are lacking. Increased frequency of eye exams may be considered in patients with long-term poor glycemic control who experience an acute dramatic improvement in A1C (27).

Metformin (31), sulfonylureas (18), and insulin therapy (in both type 1 [19] and type 2 diabetes [17]) have all been shown to reduce the rate of retinopathy. There is some evidence that metformin is more beneficial than other treatments in reducing the risk of DME (32). Glucagon like-peptide 1 receptor agonists do not appear to have specific retinopathy-related benefits over other antidiabetic medications, and one—semaglutide—may cause worsening of retinopathy, although these effects are still being studied (33). There are limited data on the effect of treatment with sodium–glucose cotransporter 2 inhibitors on retinopathy risk, although existing data seem favorable, especially with regard to DME (34,35). Thiazolidinediones have been reported to increase the risk of DME (32,36), but not all studies have supported this finding (37). Therefore, the choice of drugs for individual patients should be made based on efficacy and tolerance, rather than on the basis of eye-specific considerations.

Hypertension is also a risk factor for DR, and treatment of hypertension reduces the risk of retinopathy progression (38,39). ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics all appear to be equally beneficial in reducing the risk of progression of DR. Certain diuretics may be of benefit in DME; however, conclusive data are lacking (40). Thus, ocular status does not dictate the choice of drugs for hypertension in people with diabetes.

In addition to hypertension, the presence of other microvascular complications such as diabetes-related nephropathy and neuropathy are known risk factors for DR (41).

Statin therapy has been shown to reduce the risk of DME (42), but the impact of statins on the development and progression of retinopathy is unclear.

Hypertriglyceridemia has also been associated with DME (42), and treatment with fenofibrate reduced retinopathy in both the ACCORD and the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trials (17,43). Lipid therapy in people with diabetes should be based on established guidelines.

Initiation of either hemodialysis or peritoneal dialysis for renal insufficiency may be associated with improvement in DME, likely due to reduction in fluid volume and systemic uremia (44–46). Similarly, administration of furosemide in a patient with nephrotic syndrome has been reported to cause partial resolution of DME, although conclusive data on the use of diuretics are lacking (47).

Comprehensive diabetes self-management education and support (DSMES) has been shown to lower A1C, improve rates of screening for complications, and reduce all-cause mortality (48). DSMES is recommended at diagnosis, annually, and as needed for complications and transitions of care (48).

Data are mixed on the impact of bariatric surgery on the development and progression of retinopathy (49). This is understandable given that obesity is not a direct cause of retinopathy, but rather an indirect cause in some, but not all, cases. Also, the rapid improvement in hyperglycemia that occurs in some instances immediately after bariatric surgery may have short-term detrimental effects on retinopathy, and more frequent eye screening exams may be considered (50).

Regular exercise and increased physical activity have many health benefits, which may include a reduction in retinopathy (51,52). Any activity resulting in a Valsalva maneuver (e.g., heavy lifting) may precipitate a vitreous hemorrhage in patients with unstable proliferative retinopathy, although the benefits of exercise are likely to outweigh the low potential risk (53,54). Thus, consultation with an ophthalmologist may be warranted prior to starting vigorous exercise.

Obstructive sleep apnea is associated with retinopathy, and its treatment may reduce the risk of retinopathy development and progression (55,56).

Smoking increases the risk of retinopathy and proliferative retinopathy in people with type 1 diabetes, although this finding was not confirmed in people with type 2 diabetes (57). Smoking has also been associated with a reduced risk of DME, whereas alcohol intake seems to be associated with an increased risk of DME (58).

Several studies have shown no association between the use of aspirin and the risk of progression of DR (59,60). Little is known regarding the effects of other anticoagulants, but restricting the use of anticoagulants in patients with DR is not typically recommended.

Pregnancy can transiently but rapidly exacerbate DR (61–63), so increased surveillance is recommended, with eye exams in each trimester and postpartum (64).

The presence of DME and proliferative retinopathy is associated with increased risk of fatal and incident cardiovascular disease events (10). Nonproliferative and proliferative retinopathy are also associated with peripheral arterial disease (65), suggesting that patients with DR and DME may need more vigilant surveillance for vascular disease.

Optimizing medical management of both type 1 and type 2 diabetes is essential in preventing the development and progression of DR. Lifestyle interventions and improved control of hyperglycemia, hypertension, hyperlipidemia, and renal insufficiency can all positively affect retinopathy outcomes. In addition, it is important to remember that the presence of DR is associated with an increased risk of cardiovascular disease events, and frequent surveillance for vascular disease may be warranted.

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Dualities of Interest

T.W.G. has received research support from Zebra Biologics and consulting fees from Novo Nordisk.

C.C.W. has received research support from Adverum, Allergan, Apellis, Clearside, Genentech, Roche, Neurotech, Novartis, Opthea, Regeneron, Regenxbio, Samsung, and Santen; is a consultant for Adverum, Alimera Sciences, Allegro, Allergan, Apellis, Bayer, Clearside, EyePoint, Genentech, Kodiak, Novartis, Regeneron, Regenxbio, and Roche; and is a speaker for Regeneron.

B.A.C. has been a speaker for Novo Nordisk and served on an advisory board for Regeneron.

No other potential conflicts of interest relevant to this compendium were reported.

Acknowledgments

Editorial and project management services were provided by Debbie Kendall of Kendall Editorial in Richmond, VA.

Author Contributions

All authors researched and wrote their respective sections. Lead author T.W.G. reviewed all content and is the guarantor of this work.