The use of anti–vascular endothelial growth factor injections has been linked to an increased risk of mortality in patients with diabetic retinopathy in a new study, sounding a note of caution regarding the cardiovascular safety of these agents in clinical practice, an investigator said.
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There was no increased risk of MI or stroke risk associated with intravitreal anti-VEGF injections versus steroid injections or laser photocoagulation in the study, which was based on analysis of health records for more than 60,000 treated individuals.
However, a “signal” was observed for increased risk of death from any cause among patients receiving anti-VEGF injections, and especially so in those with a history of cardiovascular events, said investigator Miin Roh, MD, PhD, a retina surgeon and instructor in ophthalmology at Harvard Medical School, Boston.
“This study suggests that we would have to be very careful in giving anti-VEGF injections in patients for diabetic retinopathy, especially when you’re giving it for a long-term period,” Dr. Roh said in a virtual presentation at the annual scientific sessions of the American Diabetes Association.
Report of a mortality signal
The study by Dr. Roh and colleagues included patients with type 1 or 2 diabetes, identified in health claims databases who started intravitreal anti-VEGF injections, intravitreal steroid injections, or laser photocoagulation between 2009 and 2017.
Their analysis included 30,741 patients who received anti-VEGF injections and 30,741 matched controls who received laser or steroid treatment.
There were no differences in the primary composite outcome of MI or stroke, with 674 events in the anti-VEGF group and 708 events in the laser or steroid group over a 365-day treatment period, Dr. Roh reported.
By contrast, the investigator said she saw a signal for increased risk of all-cause mortality in analyses of secondary outcomes.
Over a 180-day treatment period, there was a “slight numerical increase” in all-cause mortality, with 144 deaths in the anti-VEGF group and 115 in the control group. That translated into a hazard ratio of 1.26 (95% confidence interval, 0.99-1.60).
Looking at a 365-day treatment period, there was an increase in all-cause mortality in the anti-VEGF group that this time was statistically significant, she said, with 311 and 236 events, respectively (HR, 1.32; 95% CI, 1.12-1.57).
The mortality signal was especially strong among individuals who had a prior history of a cardiovascular event, according to Dr. Roh.
In patients with cardiovascular disease history, there were 219 deaths from any cause in the anti-VEGF group and 153 in the laser or steroid group (HR, 1.44, 95% CI, 3.10-11.22) over a 365-day period, the investigator reported. By comparison, in patients with no cardiovascular disease history, there were 95 and 96 deaths (HR, 1.00; 95% CI, 0.75-1.33).
More research needed
Although these findings are “hypothesis generating,” exploration of other datasets would be warranted to measure mortality risk among patients receiving treatment for diabetic neuropathy, said Robert Gabbay, MD, PhD, chief scientific and medical officer of the ADA.
“It’s something that we need now to study more rigorously,” Dr. Gabbay said in an interview. “It doesn’t prove that there’s a connection, but it tells us that this is worth studying.”
The current study is not a randomized comparison, which means that the people chosen to receive anti-VEGF therapy, as opposed to steroid injections or laser treatment, may differ in other ways that are associated with mortality, he said.
“It’s always good to monitor these patients,” Dr. Gabbay added. “The good news is that these individuals typically are coming in, oftentimes monthly for repeated injections, and so there’s an opportunity to monitor any changes.”
Dr. Roh reported that she is a coinvestigator in a Boehringer Ingelheim–initiated study that is not directly related to the topic of this research.