Risk of diabetic retinopathy and diabetic macular oedema with sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database
Open accessAbstract
Aims/hypothesis: A protective role of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. Methods: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n =176,409; GLP1-ra + insulin, n =207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n =1,922,312). Kaplan–Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA 1c , BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. Results: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). Conclusions/interpretation: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated retinal imaging are required to determine the causal relationship with these therapies. Graphical Abstract:
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A retrospective cohort study using the TriNeX database found that GLP-1 RA therapy combined with insulin was associated with a higher risk of diabetic retinopathy compared to SGLT-2 inhibitor therapy with insulin (HR 1.21; 95% CI 1.15 to 1.26).
“A retrospective cohort studies using the TriNeX database found that GLP-1 RA therapy combined with insulin was associated with a higher risk of diabetic retinopathy (HR, 1.21; 95% CI, 1.15 to 1.26) and diabetic macular edema (HR, 1.13; 95% CI, 1.06 to 1.21) compared to SGLT-2 inhibitor therapy with insulin [93].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [93]
The same TriNeX study found that GLP-1 RA therapy combined with insulin was associated with a higher risk of diabetic macular edema compared to SGLT-2 inhibitor therapy with insulin (HR 1.13; 95% CI 1.06 to 1.21).
“and diabetic macular edema (HR, 1.13; 95% CI, 1.06 to 1.21) compared to SGLT-2 inhibitor therapy with insulin [93].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [93]
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- Authors
- Eleftheriadou, A., Riley, D., Zhao, S. S., Austin, P., Hernández, G., Lip, G. Y. H., Jackson, T. L., Wilding, J. P. H., & Alam, U.
- Affiliations
- University of Liverpool (GB)
- Manchester Academic Health Science Centre (GB)
- TriNetX (United States) (US)
- King's College London (GB)
- Corresponding author
- Alam, Uazman
- ORCID
- Venue
- Diabetologia
- Published
- 2024-04-08
- Volume
- 67
- Issue
- 7
- Pages
- 1271-1282
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC11153282
- OpenAlex
- W4394574487
- Cited by
- 73
- References
- 39
- Citations by year
- 2026: 30 · 2025: 31 · 2024: 12
- FWCI
- 24.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (ACF-2014-07-005, CL-2020-06-006, CL-2020-06-001)
- European Association for the Study of Diabetes
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- diabetic retinopathy, diabetic macular edema, SGLT2 inhibitors, GLP-1 receptor agonists, type 2 diabetes, insulin therapy, drug safety, real-world evidence, pioglitazone, metformin, antidiabetic drugs, microvascular complications, chronic kidney disease
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Aged, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Female, Humans, Hypoglycemic Agents, Insulin, Macular Edema, Male, Middle Aged, Retrospective Studies
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