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

Abstract

Background: Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. GLP-1 receptor agonists (RA) lower glucose, but 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 6 placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. Study Selection: Published trial reports were used as 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 to 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 is unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy.