In this retrospective examination of pooled adverse events from AMD studies, subjects with diabetes, although more susceptible to disease-related ocular and thromboembolic events, had no increased risk as a result of pegaptanib 0.3 mg therapy compared with those without diabetes. Since only 10% of all subjects had diabetes, comparisons between them and those without diabetes were, at best, unbalanced. Given this limitation, we found no notable differences between the subjects with and without diabetes in the frequencies of events in general or in particular events related to diabetes that were reported. Differences identified between the groups involving adverse events that occurred more often in subjects with diabetes were either expected or were not considered important. The proportions of subjects with diabetes reporting prespecified ocular adverse events were similar to or less than the corresponding proportions reported in the nondiabetic population. The reporting rate and incidence of the prespecified nonocular events (hypersensitivity reactions) were similar between the 2 groups.
The proportions of subjects with diabetes with prespecified APTC adverse events were considered similar to the proportions of those without diabetes with APTC events. However, differences in individual arterial thromboembolic adverse event terms between the 2 populations were identified. Cerebrovascular accident and myocardial infarction were reported with a slightly higher frequency in the subjects with diabetes. There were also 3 events only reported by the diabetic population: coronary artery atherosclerosis, thrombosis, and silent myocardial infarction. In addition, a comparison of nonocular medical histories between the populations indicated that metabolic, vascular, and cardiac disorders were reported more often in the subjects with diabetes, and these disorders were consistent with those generally experienced by a population with a history of diabetes. Based on the deaths reported, there did not appear to be any increased risk of death to subjects with diabetes mellitus as a result of pegaptanib treatment.
Although involving only a small population of people with diabetes receiving sham treatment, these results were further confirmed in the pooled analysis of the 3 studies in which subjects with diabetes were treated with sham injections. Overall, there was no difference in the occurrence of APTC events between subjects with diabetes receiving sham injections and those receiving pegaptanib in the pooled analysis of 9 studies.
As the known properties of VEGF include angiogenesis, increased vascular permeability, and maintenance of vascular endothelial integrity, there are a number of theoretical risks that may be associated with systemic anti-VEGF activity . The systemic administration of high dose bevacizumab in early clinical trials in oncology was associated with potential complications of hypertension, proteinuria, impaired wound healing, gastrointestinal perforation, hemorrhage and thrombosis . The systemic VEGF inhibition effects with pegaptanib are not expected due to VEGF165 selectivity and low systemic concentrations following intravitreal administration. In the present study, although the frequency of APTCs was low in both groups, subjects with diabetes appeared to be at an elevated risk of certain APTC adverse events compared to those without diabetes. Thus, the potential for systemic effects following treatment for AMD may be of greater concern in this population. In a 3-year safety study of pegaptanib, there were no thromboembolic cardiovascular accidents or nonocular hemorrhagic events following continuous treatment  while in a pooled analysis of data from the ranibizumab trials there was a significantly increased risk of cardiovascular accidents  and nonocular hemorrhages  in the treated group compared to sham. Bevacizumab has been used increasingly off-label for treatment of AMD ; the risk of these side effects following intravitreal injection are not known due to the lack of systematic reporting [25–27]. Of note, in a study of individuals with type 2 diabetes undergoing vitrectomy following intravitreal injection of bevacizumab, mean plasma VEGF concentrations were reduced approximately 10-fold (from 92.0 to 9.7 pg/ml) 1 day after injection, clearly demonstrating entry into the systemic circulation .
This retrospective examination of pooled adverse events from AMD studies has certain strengths and limitations. Its strengths include the large multinational population from which the analysis is derived and the rigorous study conduct and monitoring of adverse events in these populations. As noted above, however, the difference in size between the group with diabetes and the group without did not provide a balanced comparison in terms of numbers. Other limitations include combining study protocols that were of differing designs and lengths and pooling clinical studies that were conducted over a period of many years.