HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression

Abstract

BACKGROUNDLong-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. PURPOSETo examine the associations between retinopathy, HbA 1c , systolic blood pressure (SBP), and weight in GLP-1RA CVOTs. DATA SOURCESSystematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. STUDY SELECTIONPublished trial reports were used as the primary data sources. DATA EXTRACTIONHbA 1c , SBP, and weight data throughout follow-up by treatment group were extracted. DATA SYNTHESISRandom-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 (I 2 5 52.2%; Q statistic P 5 0.063). Univariate meta-regression showed an association betweenretinopathyandaverageHbA 1c reductionduringtheoverallfollow-up(slope 5 0.77, P 5 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA 1c showed a relationship at 3 months (P 5 0.006) and 1 year (P 5 0.002). A 0.1% (1.09 mmol/mol) increase in HbA 1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively. LIMITATIONSCVOTs were not powered to assess retinopathy outcomes and differed in retinopathyrelated criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy. CONCLUSIONSHbA 1c reduction was significantly associated with increased retinopathy risk in metaregression for GLP-1RA CVOTs. The magnitude of HbA 1c 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 whenintensifying glucose-loweringtherapy.

Understanding the place for GLP‐1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

“…Sub‐analysis has found that this increased risk is driven by rapid reduction in HbA1c in insulin‐treated patients with diabetic retinopathy, long‐standing disease and high HbA1c levels at baseline 55 . While the CVOTs (details below) were not powered or designed to assess retinopathy outcomes, a meta‐analysis of the CVOTs found that the degree of HbA1c reduction was correlated with the risk of retinopathy progression 56 . The upcoming FOCUS trial will clarify a potential link as well as establish the role of sc.…”

Glucagon-Like Peptide 1 Receptor Agonists – Potential Game Changers in the Treatment of Glaucoma?

“…Sterling et al (2021) linked the exposure to GLP-1R agonists ( i.e., dulaglutide, liraglutide, lixisenatide, exenatide , and semaglutide ) to a low risk of developing open-angle glaucoma ( Sterling et al, 2021 ). However, previous studies have raised concern that treatment with GLP-1R agonists may increase the risk of diabetic retinopathy, making them less favorable to be used against diabetic eye complications ( Diabetes Control and Complications Trial Research Group, Nathan et al, 1993 ; No authors listed, 1998 , 1999 ; Aiello and Dcct/Edic Research Group, 2014 ; Green et al, 2015 ; Marso et al, 2016b ; Jingi et al, 2017 ; Tang et al, 2018 ; Bain et al, 2019 ; Lim et al, 2019 ; Bethel et al, 2021 ). Nevertheless, this effect of GLP-1R agonists is most likely caused by a rapid decrease in patients’ blood glucose levels as discussed later ( Vilsbøll et al, 2018 ; Bain et al, 2019 ; Lim et al, 2019 ).…”

“…Previous studies, including the DCCT, SUSTAIN-6, LEADER and TECOS trials, have linked exposure to incretin-based therapies and other hypoglycemic agents (i.e., insulin , injectable semaglutide, liraglutide , and oral sitagliptin ) to the exacerbation of pre-existing retinopathy ( Diabetes Control and Complications Trial Research Group, Nathan et al, 1993 ; No authors listed, 1998 , 1999 ; Aiello and Dcct/Edic Research Group, 2014 ; Green et al, 2015 ; Marso et al, 2016a , b ; Jingi et al, 2017 ; Tang et al, 2018 ; Bain et al, 2019 ; Lim et al, 2019 ; Bethel et al, 2021 ). For example, the SUSTAIN-6 trial showed that the risk of retinopathy events was increased during the first 2 months of treatment with injectable semaglutide.…”

“…Thus, several clinical studies have linked the use of DPP4-inhibitors to either a reduced odds of diabetic retinopathy or a reduced risk of diabetic retinopathy progression (Ott et al, 2014;Kim et al, 2018;Wang et al, 2018;Chung et al, 2019;Fan et al, 2020). Nathan et al, 1993;No authors listed, 1998No authors listed, , 1999Aiello and Dcct/Edic Research Group, 2014;Green et al, 2015;Marso et al, 2016b;Jingi et al, 2017;Tang et al, 2018;Bain et al, 2019;Lim et al, 2019;Bethel et al, 2021).…”

How glucagon-like peptide 1 receptor agonists work

“…During the first month of the trial, most events coincided with a rapid and massive drop in HbA1c in dysregulated patients with pre-existing retinopathy. A recent CVOT meta-analysis showed that the magnitude of HbA1c reduction was correlated with retinopathy risk and was not associated with GLP-1RA treatment per se ( 50 ). However, a direct and unknown action of GLP-1RAs cannot be excluded.…”