In this nationwide, retrospective cohort study utilizing the Korean NHIS database, we observed a positive association between use of DPP4 inhibitors and development of DR in T2DM patients. To our knowledge, this is the first study to assess the development of DR according to use of hypoglycemic agents and to find the potential hazard of DPP4 inhibitors increasing DR in a robust, real-world population. This nation-wide population based clinical data are consistent with the biologic hypothesis that DPP4 inhibitors may accumulate SDF-1 and induce angiogenesis and retinal vasculopathy . Previous studies have reported several beneficial effects of DPP4 inhibitors, which have not been confirmed by several large clinical trials suggesting non-inferiority to non-DPP4 inhibitor medications. Neither basic nor clinical studies have paid attention to or evaluated the impact of DPP4 inhibitors on DR. Despite the innate limitations that arise from a retrospective analysis, we were able to obtain some novel findings that have not been previously addressed in any other trial. Although hypothesis generating at best, we believe that our findings warrant further analysis and investigation.
DPP4 inhibitors have only been on the market for around 10 years, but their use as a second line drug in T2DM patients has exploded due to its efficacy and lack of side effects. We however, previously published results of molecular and cellular biologic experiments with validation in animal study, where we raised concerns about DPP4 inhibitors and suggested that use of DPP4 inhibitors mechanistically may be related to increased permeability in mouse retinal arteries . In order to investigate this issue further, we utilized medical claims data from the Korean NHIS database to study the association between DPP4 inhibitors and development of DR.
In the present study, DPP4 inhibitor prescription was associated with a 9% increase in risk of developing DR in Korean T2DM patients. Oral hypoglycemic agents act in different pathways to lower blood glucose, and although all agents have the same goal, side effects vary among drug types. The increased risk of developing DR may be explained due to effects that the drug has on vascular permeability and angiogenesis as we showed in our previous study . DPP4 inhibitors increase SDF-1 and Src-induced tyrosine phosphorylation of VE-cadherin, which in turn leads to increased vascular permeability and neovascularization . Although previous studies have reported that use of DPP4 inhibitors are protective against development of microvascular complications in diabetic patients, they have failed to show a specific mechanism other than glucose lowering to support the results. We have previously reported that DPP4 inhibitors increase vascular permeability in mice retinal arteries, which is the first step in the development of DR. Although the negative effects of DPP4 inhibitors might be partially neutralized by improved glucose lowering capabilities, our results show that the use of DPP4 inhibitors could be associated with poor long term ocular outcomes.
The benefit of tight glucose control on macrovascular or cardiovascular complications have been investigated in several previous trials [11, 12]. In terms of microvascular complications, landmark prospective trials like the UK Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCT) have reported that every 1% reduction in HbA1c correlated to 37% and 54% reduction in risk of microvascular complications, respectively [13, 14]. But the effect of DPP4 inhibitors on microvascular complications have not been well evaluated. Two animal studies suggested positive effects of DPP4 inhibitors on diabetic nephropathy [15, 16]. One small clinical study suggested that saxagliptin treatment just for 6 weeks may change retinal arteriolar structure or retinal capillary flow .
Although there have been no reports of definite association between DPP4 inhibitors and ocular complications, the TECOS trial has reported a significant higher incidence of diabetic eye disease (RR 1.25, 95% CI 1.04–1.50) compared with placebo . Furthermore, use of glucagon-like peptide-1 (GLP-1) analogues, also an incretin-based therapy, were associated with increased incidence of DR in SUSTAIN-6 and LEADER trials [19, 20]. Although the mechanism of action of DPP4 inhibitors are different from that of GLP-1 analogues, when the results of the current analysis are taken together with the results of our preclinical study, we cannot ignore the possibility of DPP4 inhibitors to increase the risk of development of DR. There is no doubt in the fact that ‘the glucose-lowering effect’ of DPP4 inhibitors will have beneficial effects in preventing DR. However, it may have ‘the adverse extra-glucose effects’ that warrant further clinical investigation. If similar results are reproduced in other diabetic cohorts, physicians may need to be more vigilant in monitoring DR progression in patients receiving DPP4 inhibitors.
However, there have been no definite studies linking either glucose control and DR or certain hypoglycemic agent and DR in a large and long-term population-based cohort. Our cohort study followed up over 500,000 patients for a mean period of 2.3 years, and could be a reference for the future treatment strategies of T2DM and its complications especially DR.
Our study population generally represents patients in the early stages DM, with over 75% having a disease duration less than 5 years. Patients with previous history suggesting DR were excluded from the study. According to our analysis, although DPP4 inhibitors were associated with increased risk of DR, it was also associated with reduced risk of death and cardiovascular disease such as MI and ischemic stroke. In our analysis, patients on DPP4 inhibitors were associated with a reduced risk of cardiovascular (CV) outcomes, which is in discordance with previous large-scale trials, where DPP4 inhibitors have failed to show any CV benefit [18, 21, 22]. Few studies have shown good results on the CV risk of DPP4 inhibitors. Prior to the publication of the major randomized controlled trials dealing with DPP4 inhibitors, there was a meta-analysis showing the reduction of CV risk by DPP4 inhibitors . The post-hoc analysis of randomized controlled EXAMINE trial with alogliptin showed that alogliptin could reduce the risk of CV death in a group with the normal renal function, but not in patient with impaired renal function . In the present study, as opposed to previous studies of DPP4 inhibitors [18, 21, 22] but similar to meta-analysis and post-hoc analysis [23, 24], the reduced risk of DPP4 inhibitors may have been driven by better baseline characteristics in DPP4 inhibitor group than in the non-DPP4 inhibitor group. Despite having better baseline characteristics and clinical outcomes of cardiovascular events in the DPP4 inhibitor group, the high prevalence of retinopathy in the DPP4 inhibitor group suggests an association between DPP4 inhibitors and retinopathy. Further prospective studies related to retinopathy are needed.
There are several limitations to this study. As the study was retrospective in its design, utilizing data from insurance claims, it lacks results such as HbA1c and fasting glucose levels. Thus, we were unable to assess the disease state of each patient. Second, there was also no data on compliance or the effectiveness of the prescribed medications for the patients. Third, the outcome events were captured through pre-defined criteria from the claims data. The failure to screen patients for DR or failure to input correct diagnostic codes might have led to underestimation of events, which are innate to these types of analyses. The rate of ischemic stroke was generally high in our study population, which might be due to input of unconfirmed diagnostic codes. Fourth, although we tried our best to adjust for significant baseline differences, the two groups were mostly heterogeneous. Finally, this study was not designed to assess the causal relationship. At best, our findings are positive association between prescription of DPP4 inhibitors and DR, and thus the results should be interpreted with caution. Long term data from randomized and prospective trials are needed to better understand the causal relationship between DPP4 inhibitors and DR.