Risk of Diabetic Retinopathy between Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists (Diabetes Metab J 2023;47:394-404)

See the reply "Risk of Diabetic Retinopathy between Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists (Diabetes Metab J 2023;47:394-404)" in Volume 47 on page 573.

See the article "Risk of Diabetic Retinopathy between Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists" on page 394.

Diabetic retinopathy (DR) is a well-known microvascular complication that can cause blindness and reduce quality of life. Although glucose lowering can delay the development and progression of DR, there is no established medication to prevent DR [1]. This study is a target trial with a large real-world database to compare the prevention of DR outcomes between sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) in new users.

In this article, the incidence of any DR was comparable between groups treated with SGLT2is and GLP1-RAs [2]. However, the SGLT2i group showed a lower risk of proliferative DR and composite surgical outcomes suggestive of vision-threatening DR. Additionally, this real-world data-based study showed consistent results among all subgroups, which proved its internal validity.

However, there are some questions that need to be explored. Firstly, the SGLT2i and GLP1-RA groups were heterogeneous in terms of baseline demographics. The number of SGLT2i users was more than 10 times greater than that of GLP1-RA users. Moreover, the SGLT2i group showed lower glycosylated hemoglobin, a shorter duration of diabetes, and lower rates of other microvascular complications such as nephropathy and neuropathy. Considering that DR, especially advanced DR, may increase as the severity and duration of diabetes increase [3], the role of SGLT2is in lowering the risk of DR may be overestimated compared to GLP1-RAs in this study. Although the inverse probability of treatment weighting method was applied, there may still be other confounding factors.

Secondly, patients less than 40 years old were excluded. Recently, the number of young adults up to age 40 with type 2 diabetes mellitus has been rapidly increasing, and early detection and proactive management are needed to prevent microvascular complications [4]. Many studies have found that the prevalence of DR decreases with increasing age, and a higher incidence is seen in younger patients with diabetes [5]. This trend suggests that younger patients with diabetes are more likely to suffer from DR and develop advanced DR in old age. Thus, studies on younger patients with diabetes for the prevention of various diabetic complications, including retinopathy, are needed.

Thirdly, the validity of the DR outcomes used in this study is still in question. As the authors mentioned, according to a systematic review and meta-analysis of randomized controlled trials, there was no significant difference in DR outcomes between SGLT2is and placebo [6]. Unlike this study, which set the primary outcome as any DR, nonproliferative DR, proliferative DR, and vitreoretinal interventions in a retrospective manner, focusing on the prevention of retinopathy, the previous meta-analysis included a broader range of diabetic ocular diseases, such as blindness, macular edema, vitreous hemorrhage, or detachment, suggesting more severe forms of ocular complications. However, further studies are needed to determine which definition is more appropriate in the prevention and management of DR.

Lastly, although possible mechanisms of DR prevention by SGLT2is were suggested by the authors, the mechanisms by which SGLT2is reduce advanced DR but not earlier stages of DR have not yet been elucidated.

In conclusion, as the prevalence of diabetes and the rate of microvascular and macrovascular complications continue to rise, results indicating that SGLT2is lower the risk of proliferative DR and vitreoretinal interventions more effectively than GLP-RAs are important findings for the prevention of DR. However, further studies are necessary to investigate complications in younger patients with diabetes, establish consistent criteria for DR outcomes, and elucidate the underlying mechanisms involved.

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

1. Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 2017;5:431-7.

2. Lin TY, Kang EY, Shao SC, Lai EC, Garg SJ, Chen KJ, et al. Risk of diabetic retinopathy between sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Diabetes Metab J 2023;47:394-404.

3. Ding J, Wong TY. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 2012;12:346-54.

4. Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet 2022;400:1803-20.

5. Sabanayagam C, Banu R, Chee ML, Lee R, Wang YX, Tan G, et al. Incidence and progression of diabetic retinopathy: a systematic review. Lancet Diabetes Endocrinol 2019;7:140-9.

6. Li C, Zhou Z, Neuen BL, Yu J, Huang Y, Young T, et al. Sodiumglucose co-transporter-2 inhibition and ocular outcomes in patients with type 2 diabetes: a systematic review and metaanalysis. Diabetes Obes Metab 2021;23:252-7.