HbA1c change and diabetic retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: a meta-analysis and meta-regression
Open accessAbstract
BACKGROUND: Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes. PURPOSE: To examine the associations between retinopathy, HbA1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs. DATA SOURCES: Systematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. STUDY SELECTION: Published trial reports were used as the primary data sources. DATA EXTRACTION: HbA1c, SBP, and weight data throughout follow-up by treatment group were extracted. DATA SYNTHESIS: Random-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studies (I2 = 52.2%; Q statistic P = 0.063). Univariate meta-regression showed an association between retinopathy and average HbA1c reduction during the overall follow-up (slope = 0.77, P = 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA1c showed a relationship at 3 months (P = 0.006) and 1 year (P = 0.002). A 0.1% (1.09 mmol/mol) increase in HbA1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively. LIMITATIONS: CVOTs were not powered to assess retinopathy outcomes and differed in retinopathy-related criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy. CONCLUSIONS: HbA1c reduction was significantly associated with increased retinopathy risk in meta-regression for GLP-1RA CVOTs. The magnitude of HbA1c reduction was correlated with retinopathy risk in people with diabetes and additional cardiovascular risk factors, but the long-term impact of improved glycemic control on retinopathy was unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy.
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Increased retinopathy complications seen in the SUSTAIN 6 CVOT appear attributable to the magnitude and rapidity of HbA1c reductions in individuals with pre-existing diabetic retinopathy and high glycemic levels.
“Increased retinopathy complications seen in the SUSTAIN 6 CVOT appear attributable to the magnitude and rapidity of HbA1c reductions in individuals with pre-existing diabetic retinopathy and high glycemic levels, as has been seen in previous studies with insulin (170,171).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [171]
The Conclusions identify SUSTAIN-6 as the trial with the greatest retinopathy signal and the largest HbA1c differences at three months and later follow-up. The Results report an association between greater HbA1c reductions and retinopathy risk across trials, but the paper does not establish that this explains the SUSTAIN-6 events specifically in people with both pre-existing retinopathy and high glycemic levels. The analysis used trial-level rather than patient-level data; page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLater subgroup and mediation analyses suggested that the majority of the effect might be attributed to a large and rapid HbA1c reduction, a recognized risk factor for early worsening of diabetic retinopathy.
“Later subgroup and mediation analyses suggested that the majority of the effect might be attributed to a large and rapid glycated haemoglobin (HbA1c) reduction, a recognized risk factor for early worsening of diabetic retinopathy, 116 especially among patients with high HbA1c and baseline signs of retinopathy. 117”
From Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer <scp>GLP</scp> ‐ <scp>1RA</scp> ‐based weight‐loss therapies (2025) · cites this paper as [116]
The Results (Meta-regression; page not provided) associate greater HbA1c reduction with higher retinopathy risk, including at 3 months. The Conclusions (page not provided) describe early worsening after intensified glucose control. But this paper reports an association, not a mediation analysis showing that HbA1c reduction accounts for the majority of an effect. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHbA1c reduction was associated with increased risk of diabetic retinopathy in a meta-regression of GLP-1RA cardiovascular outcome trials.
“Instead, HbA1c reduction was associated with increased risk of diabetic retinopathy in a meta-regression of GLP-1RA cardiovascular outcome trials [27].”
From The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2024) · cites this paper as [27]
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References 32 · Cited by 151
Research works printed but not linked: 2
- [14]Bethel MA, Diaz R, Castellana N, Gerstein HC, Bhattacharya I, Lakshmanan MC The Relationship between HbA1c Change and Clinical Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcomes Trials. PROSPERO 2020 CRD42020176410. Accessed 30 October 2020. Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020176410 PMC7783944 33444163
- [25]Deeks JJ, Higgins JPT, Altman DG; the Cochrane Statistical Methods Group. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1, 2020. Chapter 10: Analysing data and undertaking meta-analyses. Specify characteristics in advance. Accessed 1 May 2020. Available from https://training.cochrane.org/handbook/current/chapter-10#section-10-11-4
- Authors
- Bethel, M. A., Diaz, R., Castellana, N., Bhattacharya, I., Gerstein, H. C., & Lakshmanan, M. C.
- Affiliations
- Eli Lilly (United States) (US)
- Estudios Clínicos Latino América (ECLA), Rosario, Argentina
- Estudios Clínicos Latinoamérica (AR)
- Eli Lilly (India) (IN)
- Population Health Research Institute (CA)
- Corresponding author
- Bethel, M. Angelyn
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2020-12-14
- Volume
- 44
- Issue
- 1
- Pages
- 290-296
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC7783944
- OpenAlex
- W3114565741
- Cited by
- 151
- References
- 32
- Citations by year
- 2026: 22 · 2025: 43 · 2024: 44 · 2023: 25 · 2022: 10 · 2021: 7
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- Amgen
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- University of Oxford
- Novo Nordisk
- Duke Clinical Research Institute
- 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, HbA1c reduction, GLP-1 receptor agonists, glycemic control, type 2 diabetes, cardiovascular outcome trials, systolic blood pressure, weight, retinopathy risk, diabetic nephropathy, diabetic neuropathy, diabetic cardiomyopathy, cardiovascular risk factors, retinopathy screening, retinopathy progression
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Glycated Hemoglobin, Humans, Hypoglycemic Agents
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