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Patients with type 2 diabetes who received intravitreal anti-vascular endothelial growth factor (VEGF) injections for diabetic retinopathy were more likely to develop systemic adverse events (AEs) compared with those who did not receive injections, according to a retrospective, longitudinal population-based analysis.

Among over 1.7 million patients within the Veterans Health Administration, the 5-year cumulative incidence of any systemic AE was 37% in the injection group versus 18.4% in the non-injection group (P<0.001), reported Roomasa Channa, MD, of the University of Wisconsin in Madison, and colleagues.

Anti-VEGF injections were independently associated with a higher likelihood of developing any systemic AE (OR 1.8, 95% CI 1.7-1.9) after controlling for a number of factors including age, sex, race/ethnicity, severity of diabetic retinopathy, and mean hemoglobin A1c, among others, they noted in .

Specifically, anti-VEGF injections were independently associated with a higher likelihood of acute myocardial infarction (OR 1.6, 95% CI 1.5-1.7), cardiovascular disease (OR 1.4, 95% CI 1.3-1.5), and kidney disease (OR 1.8, 95% CI 1.7-1.9).

Evidence of detectable increases in systemic levels of intravitreal anti-VEGF agents have raised safety concerns, Channa and team explained, which are compounded in diabetes patients already believed to have increased risk for these AEs.

"Studying the role of intravitreal anti-VEGF therapy in contributing to systemic adverse event risk in DR [diabetic retinopathy] has been challenging," the authors wrote, noting that associations among diabetes, cardiovascular disease, and coronary artery disease are common.

In an , Brian L. VanderBeek, MD, MPH, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, cited conflicting findings from another that showed no increased risk of systemic AEs with anti-VEGF agents.

"This suggests the question of intravitreal anti-VEGF agent-associated adverse effects is still far from settled," he wrote.

While acknowledging the difficulty of finding a suitable active comparator for widely used anti-VEGF agents, VanderBeek noted that the absence of an active comparator to reduce the potential for indication bias meant that the study "only analyzed patients with type 2 diabetes and focused on adverse events that are well-known complications of diabetes."

Confounding could have also occurred due to inclusion of patients who received anti-VEGF injections for other common indications, which "have their own risk factors known to be associated with the study end points," he added. "Lastly, causal inference mandates that drug exposures occur prior to and within relative proximity to the outcome. For an adverse effect to be associated with an anti-VEGF agent, the adverse effect should occur while the agent is still in the patient's system."

For this analysis, Channa and colleagues used data from the Corporate Data Warehouse, a large-scale database of patients within the Veterans Health Administration. They included 1,731,782 patients with type 2 diabetes who were seen at any VA health facility from January 2011 through December 2012. Mean age was 63.8, 95.7% were men, and 76.1% were white.

Diabetic retinopathy was present in 27.5% of patients, and 0.8% had received anti-VEGF injections.

Systemic AEs occurring from January 2013 through December 2017 were assessed in all patients who did and did not receive anti-VEGF injections at 1-, 3-, and 5-year follow-up. Anti-VEGF agents used included aflibercept (Eylea; 48%), bevacizumab (Avastin; 35.7%), and ranibizumab (Lucentis; 8.7%).

Of the total number of patients, 18.6% developed systemic AEs between 2013 and 2017.

Patients who developed systemic AEs were older (mean 66.6 vs 63.2), were more likely to be men (97.2% vs 95.3%), were more likely to use tobacco (24.7% vs 17.0%), and a higher proportion had diabetic retinopathy (38.8% vs 24.9%).

The overall mean number of injections given to those who developed systemic AEs was 10.2 versus 10.8 for those who did not. The proportion of patients who had received an anti-VEGF injection at any point during the 5 years was higher among those who developed systemic AEs compared with those who did not (1.6% vs 0.6%, respectively, P<0.001).

In addition to the study's cohort of predominantly white men, Channa and colleagues noted that limitations included possible underestimation of systemic AEs due to exclusion of patients with a history of systemic AEs prior to starting injections, which may also limit generalizability.

"Our results show a sharp increase in coronary artery disease and kidney disease events at year 3. While this may represent a true increase in incidence of adverse events with continued or prolonged anti-VEGF use, additional studies are needed to verify and explain these findings," they wrote.

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