Impact of insulin pump therapy and islet transplantation on progression of diabetic retinopathy in Type 1 diabetes

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness worldwide and affects almost all adults with Type 1 diabetes within 20 years of diagnosis. It is well established that optimising glycaemic control reduces DR risk, however little is known about the impact of individual Type 1 diabetes treatment modalities on the incidence and progression of DR. This study examines the effects on DR progression of two treatments used in Type 1 diabetes; Continuous subcutaneous insulin infusion (CSII) therapy, and islet transplantation. Both treatments have been shown to improve glycaemic control when compared to multiple daily injections of insulin (MDI), but it has not been clearly established whether these glycaemic benefits correspond to microvascular benefits in terms of reduced DR risk. Reports of paradoxical early worsening of DR (EWDR) in people with rapid improvements in glycaemic control can complicate matters, as does the use of immunosuppressive medication in those undergoing islet transplantations. In this thesis we test the hypothesis that rapid reduction of time in hyperglycaemia and hypoglycaemia post intervention with islet transplantation or CSII therapy will be associated with changes consistent with worsening DR in the short term (consistent with reports of EWDR), but reduced retinopathy risk in the long term. In addition, we assess the use of emerging retinal imaging techniques in DR, and propose that novel retinal biomarkers will be able to detect early retinopathy changes in individuals with diabetes following the introduction of these treatment interventions. We conducted a retrospective analysis of graded DR screening data for people with Type 1 diabetes following commencement of CSII or islet transplantation, compared to continued MDI therapy. We show that in people with no or mild DR, CSII (n=204 people) is associated with significantly reduced risk of DR progression on multivariate Cox proportional hazard analysis (HR 0.56, p=0.02) over 2.3 years compared with those continuing on MDI (n=211 people). There was no significant difference in DR progression following islet transplantation compared to either CSII or MDI therapy. Furthermore, despite significant HbA1c reductions in those commenced on CSII and islet transplantation versus those continued on MDI, there was no evidence of EWDR following the addition of these therapies. Quantitative analyses of retrospectively collected DR screening images from CSII participants (n=78 at baseline) and islet transplanted participants (n= 29 at baseline) were also carried out using semi­automated software (Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE)), which was designed in Scotland for the detection and quantification of retinal vascular geometry from fundus images. We assessed three retinal biomarkers which have been proposed as early indicators of DR incidence and severity; vessel calibre, vessel tortuosity and fractal dimensions (denoting vascular branching patterns). Increases in these markers have been associated with increased DR incidence and progression in previous fundus imaging studies. We found significant reductions in fractal dimensions (p<0.001) and vessel calibre measurements (p<0.01) over a mean 3.3 year period following the introduction of CSII therapy which may signify reduced burden of DR in participants post CSII, though further studies with suitable control participants are needed to confirm these preliminary findings. There were no significant changes in these retinal biomarkers over time in islet transplant participants, though study numbers were small leading to an underpowered analysis. Finally, a prospective study was done to assess retinal biomarkers using other retinal imaging modalities; Optical Coherence Tomography (OCT), Optical Coherence Tomography Angiography (OCTA) and Ultrawide­field Scanning Laser Ophthalmoscopy (UWF­SLO), which are emerging as useful tools in DR imaging assessment. We looked at changes in vessel density, foveal avascular zone (FAZ) and acircularity index (AI) using OCTA, retinal and choroidal thickness using OCT, and vessel calibre using UWF­SLO. We found no significant change from baseline in any of these biomarkers over a 12 month follow up in 16 CSII participants, including no evidence of EWDR. However, comparison to previously collected healthy control data showed significant differences in these biomarkers in participants with diabetes compared to those without diabetes, with significant reductions in vessel density and choroidal thickness and significant increases in AI in individuals with diabetes. These findings support growing evidence of the potential value of these parameters as early markers of DR.

In conclusion, our study did not find any evidence for EWDR following the introduction of CSII therapy or islet transplantation in our cohort, despite early improvements in glycaemic control, but did find evidence for reduced DR progression in the longer term following CSII therapy, including reductions in DR biomarkers on fundus imaging. This indicates potential benefits of CSII in reducing the burden of microvascular complications due to DR in Type 1 diabetes. Though we didn’t show long term DR risk reduction in islet transplant participants, we found stable DR up to 5 years post islet transplantation compared to CSII and MDI participants, despite the addition of potentially damaging immunosuppressive therapy. Our data also supports early reports for the growing utility of retinal biomarkers derived from novel imaging modalities in the early identification of DR, particularly markers of vessel density, choroidal thickness and AI. Further larger prospective studies will help characterise the full significance of these markers and their future potential in DR assessment and intervention.