Early worsening of diabetic retinopathy with insulin and incretin-based therapies is not a consequence of rapid glucose lowering but an insulin-linked angiogenic and inflammatory phenomenon—mislabeling it as a glycemic effect risks therapeutic inertia and undermines long-term retinal protection.

Lu M (2026) Time to Retire the Glycemic Dogma of Early Worsening in Diabetic Retinopathy. J Endocrinol Diabetes Obes 12(1): 1128.

Early worsening of diabetic retinopathy with insulin and incretin-based therapies is not a consequence of rapid glucose lowering but an insulin-linked angiogenic and inflammatory phenomenon—mislabeling it as a glycemic effect risks therapeutic inertia and undermines long-term retinal protection.

The long-standing belief that early worsening of diabetic retinopathy (DR) is driven by the rapidity or magnitude of hemoglobin A1c (HbA1c) reduction has outlived its explanatory power [1, 2]. While historically convenient, this dogma no longer withstands scrutiny in the context of modern antidiabetic therapies [3]. Persisting with this explanation risks misinterpreting contemporary clinical data and, more importantly, misguiding patient care.if early worsening were truly driven by the rapid normalization of glucose, retinal outcomes would align predictably with glycemic kinetics. They do not. Sodium glucose cotransporter-2 inhibitor empagliflozin lowers plasma glucose quickly and produces early decline in HbA1c yet demonstrates protective effects on the retina [4]. In contrast, semaglutide—titrated slowly and associated with a gradual reduction in HbA1c—has been linked to transient worsening of DR [5]. Similarly, dipeptidyl peptidase-4 (DPP-4) inhibitors, despite only modest glycemic efficacy, show early worsening signals (6). Metformin, by comparison, typically achieves greater HbA1c reductions than DPP-4 inhibitors but does not trigger early deterioration (7). These observations are not outliers; rather, they form a coherent and internally consistent pattern that argues strongly against a purely glycemic explanation.

The angiogenesis–inflammation hypothesis offers a more biologically credible framework [3]. Insulin is not a passive intermediary of glucose control, but a potent signaling hormone with direct retinal effects [3, 8, 9]. Experimental data demonstrate that insulin upregulates vascular endothelial growth factor and angiopoietin-2, disrupts the blood–retinal barrier, and amplifies inflammatory cascades, particularly in insulin-resistant states marked by hyperinsulinemia [8-10]. Under this model, early worsening of DR is not a function of glucose correction per se but an insulin-linked phenomenon— whether insulin is administered exogenously or stimulated endogenously by secretagogues, including sulfonylureas, DPP-4 inhibitors, and glucagon-like peptide-1 receptor agonists [1-3, 5, 6].

Crucially, abandoning the glycemic-kinetics dogma does not undermine the foundational role of hyperglycemia in DR pathogenesis. On the contrary, it clarifies a long standing paradox [3]. Early worsening is transient, mechanistically distinct, and ultimately eclipsed by the dominant long-term benefit of sustained glycemic control, as conclusively demonstrated in DCCT and UKPDS trials [1, 11-13]. Lowering HbA1c substantially remains the key driver of durable, decades-long retinal protection, termed “metabolic memory” in DCCT/EDIC and the “legacy effect” in UKPDS [12, 13]. Continued reliance on an outdated explanatory model carries real clinical consequences. It encourages therapeutic hesitation, fosters unwarranted fear of highly effective agents, and shifts attention away from actionable risk-mitigation strategies. A mechanism based understanding reframes the clinical task: not to slow or dilute effective therapy, but to deploy it intelligently—through gradual titration, combination with insulin-independent agents that dampen angiogenic and inflammatory signaling, and rigorous retinal surveillance during vulnerable periods.

Modern diabetes care demands modern pathophysiology. As insulinotropic therapies are increasingly used earlier, more aggressively, and in patients with established microvascular disease, the field must move beyond reflexive attribution to “rapid HbA1c lowering” [3, 14]. Early worsening of DR should be recognized for what it is: a pathway-specific, insulin mediated biological effect, not a warning against effective glycemic control. Retiring this dogma is not semantic—it is essential for aligning metabolic innovation with durable visual outcomes [3].

The author, Lu, reports no conflicts of interest or financial relationships with industry. Ethics, Consent to Participate, and Consent to Publish declarations are not applicable for this perspective.

1. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, 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: 977-986.
2. Bain SC, Klufas MA, Ho A, et al. Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes Obes Metab. 2019; 21: 454-466.
3. Lu M. Angiogenesis and inflammation in the retinopathy risk of insulin and semaglutide - a review. Int J Retina Vitreous. 2026; 12:67.
4. Tesfaye H, Paik JM, Roh M, et al. Empagliflozin and the Risk of Retinopathy in Patients with Type 2 Diabetes. JAMA Ophthalmol. 2025; 143: 62-71.
5. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016; 375: 1834-1844.
6. Kim NH, Choi J, Kim NH, et al. Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: A population-based study. Diabetes Metab. 2018; 44:361-367.
7. Li Y, Ryu C, Munie M, et al. Association of Metformin Treatment with Reduced Severity of Diabetic Retinopathy in Type 2 Diabetic Patients. J Diabetes Res. 2018; 2018:2801450.
8. Lu M, Amano S, Miyamoto K, et al. Insulin-induced vascular endothelial growth factor expression in retina. Invest Ophthalmol Vis Sci. 1999; 40: 3281-3286.
9. Poulaki V, Qin W, Joussen AM, et al. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J Clin Invest. 2002; 109: 805-815.
10. Chandel S, Sathis A, Dhar M, et al. Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2. Atherosclerosis. 2020; 307: 1-10.
11. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352: 837-853.
12. Aiello LP; DCCT/EDIC Research Group. Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014; 37: 17-23.
13. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359: 1577-

14. 1589. Drucker DJ. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. Diabetes Care. 2024; 47: 1873-1888.