Anti-VEGFs May Increase the Risk of Systemic Adverse Events in People with Diabetes

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Intravitreal anti-VEGF injections were associated with an increase in the likelihood of systemic adverse events among patients with diabetic retinopathy.

New research identified an association between intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections with an increase in the likelihood of systemic adverse events among patients with diabetic retinopathy (DR).1

Results showed the proportion of patients with any systemic adverse event, including myocardial infarction, cardiovascular disease, and kidney disease, was higher in the anti-VEGF injection group than the non-injection group at year 5; however, the difference in overall number of given injections among those who did or did not develop systemic adverse events was small (10.2 vs. 10.8, respectively).

“This association was maintained when controlling for several factors, including age, sex, race, ethnicity, smoking status, mean hemoglobin A1c levels, statin use, DR severity, and comorbidity burden,” wrote the investigative team, led by Roomasa Channa, MD, from the department of ophthalmology and visual sciences at the University of Wisconsin.

Ocular complications resulting from DR and diabetic macular edema (DME) are a leading cause of visual loss in adults, with management of the diseases evolving from laser photocoagulation to the administration of anti-VEGF agents. Previous literature has suggested the potential for serious systemic effects of VEGF inhibition, raising safety concerns for high-risk patient populations, such as those with diabetes. However, data on the systemic safety of intravitreal anti-VEGF injections among patients with diabetes remain inconclusive.

To better address this knowledge gap, the current retrospective, longitudinal analysis explored the systemic safety of anti-VEGF among patients with diabetes from the Corporate Data Warehouse within the US Veteran Affairs (VA) health care program. All patients 18 years and older with a diagnosis of type 2 diabetes or DR seen at any VA health care facility between January 2011 - December 2012 were included in the analysis. The investigative team then extracted data to identify systemic adverse events in the patient cohort from January 2013 - December 2017.

The analysis included all individuals with diabetes (either with or without DR) who did and did not receive anti-VEGF injections. Meanwhile, those with a history of prior systemic adverse events and those who received an intravitreal injection between January 2011 - December 2012 were excluded from the analysis. Channa and colleagues extracted data on age, sex, ethnicity, self-reported race, tobacco use) presence and severity of DR, anti-VEGF injection history, and comorbidity burden (Deyo-Chalson Comorbidity Index [DCCI]).

The primary outcome for the analysis was the proportion of patients with any incident systemic adverse event, acute myocardial infarction, cardiovascular disease (CVD), or kidney disease at 1-, 3-, and 5-year follow-up. Investigators summarized baseline characteristics for the entire cohort, for patients who received anti-VEGF injections, and those who did not receive injections. Univariable and multivariable analyses identified factors associated with the occurrence of systemic events in the entire cohort and the injection group.

A total of 1,731,782 patients with T2D (mean age, 63.8 years; 1,656,589 [95.7%] male) met inclusion criteria and were included in the analysis. Of this cohort, 476,013 patients (27.5%) had DR and 14,022 (0.8%) received treatment with anti-VEGF injections. Upon analysis, the analysis showed 321,940 (18.6%) patients in the total cohort developed systemic adverse events between 2013 - 2017.

Investigators found patients who developed systemic adverse events were older (mean, 66.6 years vs 63.2; P < .001), more likely to be male (97.2% vs 95.3%; P < .001), more likely to use tobacco (24.7% vs 17.0%; P < .001), and a higher proportion had DR (38.8% vs 24.9%; P < .001). Moreover, the proportion of patients who received an anti-VEGF injection at any point during the 5 years was found to be higher among those who developed systemic adverse events (1.6% vs. 0.6%; P <.001).

The analysis showed the 5-year cumulative incidence of any systemic adverse event was 37.0% (n = 5187 of 14,022) in the anti-VEGF injection group versus 18.4% (n = 316,753 of 1,717,760) in the non-injection group (P <.001). Anti-VEGF injections were additionally independently associated with a higher likelihood of any systemic adverse event (odds ratio [OR], 1.8; 95% CI, 1.7 - 1.9), including acute myocardial infarction, CVD, and kidney disease, after controlling for all relevant variables.

“Alternative therapies, such as intravitreal steroids or laser, may be an option for patients with diabetes who are at high risk of systemic adverse events,” investigators wrote.


Zafar S, Walder A, Virani S, et al. Systemic Adverse Events Among Patients With Diabetes Treated With Intravitreal Anti-Vascular Endothelial Growth Factor Injections [published online ahead of print, 2023 Jun 1]. JAMA Ophthalmol. 2023;10.1001/jamaophthalmol.2023.2098. doi:10.1001/jamaophthalmol.2023.2098