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Aims: Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models.Methods: We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice.Results: In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800-1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization.Conclusions: The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

Both the presence of diabetic retinopathy and its severity are significantly associated with future cardiovascular (CV) events. Whether its progression is also linked to incident CV outcomes hasn't been assessed. The relationship between retinopathy, its 4-year progression, and CV outcomes (CV death or nonfatal myocardial infarction or stroke) was analyzed in participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who also participated in the ACCORD Eye Study. Retinopathy was classified as either none, mild, moderate, or severe, and worsening was classified as a <2-step, 2-3-step, or >3-step change (that included incident laser therapy or vitrectomy). Participants (n = 3,433) of mean age 61 years had baseline retinal photographs (seven stereoscopic fields). Compared with no retinopathy, the adjusted HRs (95% CI) for the CV outcome rose from 1.49 (1.12-1.97) for mild retinopathy to 2.35 (1.47-3.76) for severe retinopathy. A subset of 2,856 was evaluated for progression of diabetic retinopathy at 4 years. The hazard of the primary outcome increased by 38% (1.38 [1.10-1.74]) for every category of change in retinopathy severity. Additional adjustment for the baseline and follow-up levels of A1C, systolic blood pressure, and lipids either individually or together rendered the relationships between worsening and CV outcomes nonsignificant. Both the severity of retinopathy and its progression are determinants of incident CV outcomes. The retina may provide an anatomical index of the effect of metabolic and hemodynamic factors on future CV outcomes.

The sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce the incidence of macrovascular complications of diabetes, while their effect on diabetic retinopathy has not been clarified. We compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP4is) on the risk of diabetic retinopathy and its progression in people with type 2 diabetes. We performed a retrospective cohort study among people with type 2 diabetes who started on a SGLT2i or DPP4i from 2014 to 2016 according to the Korean National Health Insurance Service database. Subjects initiated on a SGLT2i or DPP4i were matched on a 1:1 basis according to their propensity scores, and Cox proportional hazards regression models were used to calculate the hazard ratios for the risk of diabetic retinopathy and its progression. After propensity score-matching, 41,430 patients without a history of diabetic retinopathy were identified as new users of a SGLT2i (n = 20,175) or DPP4i (n = 20,175). The hazard ratio (95% CI) for diabetic retinopathy was 0.89 (0.83-0.97) for SGLT2i initiators compared with DPP4i initiators. In patients with a history of diabetic retinopathy (n = 4,663 pairs), there was no significant difference in diabetic retinopathy progression between SGLT2i initiators and DPP4i initiators (hazard ratio 0.94, 95% CI 0.78-1.13). This real-world cohort study showed that SGLT2is might be associated with lower risk of diabetic retinopathy compared with DPP4is. Randomized controlled trials are needed to investigate the long-term effect of SGLT2is in diabetic retinopathy in people with diabetes.

Aims/hypothesis In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. Methods From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA 1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. Results Normo- (ACR <3.4), micro- (ACR 3.4–34) or macroalbuminuria (ACR ≥34 mg/mmol) were present in 91.6%, 6.4% and 1.9% of individuals, respectively. eGFR categories 1 (≥90 ml min −1 [1.73 m] −2 ), 2 (60–89 ml min −1 [1.73 m] −2 ) and 3 (<60 ml min −1 [1.73 m] −2 ) were present in 57.3%, 39.0% and 3.7%, respectively. The majority of participants had no CKD (89.4%), while stages 1–2 and ≥3 CKD were detected in 6.8% and 3.7%, respectively. The albuminuric (Alb + ) and non-albuminuric (Alb − ) phenotypes were present in 12 (41.4%) and 17 (58.6%) individuals with stage ≥3 CKD, respectively. Individuals with an ACR <3.4 mg/mmol were subdivided into those with normal albuminuria (<1.1 mg/mmol; 77.2%) and mildly increased albuminuria (1.1–3.4 mg/mmol; 14.4%), and individuals with stage 2 CKD were subdivided into those with eGFR 75–89 ml min −1 [1.73 m] −2 and 60–74 ml min −1 [1.73 m] −2 . ACR <3.4 mg/mmol (88.7%) and even <1.1 mg/mmol (70.4%) were common in individuals with eGFR 60–74 ml min −1 [1.73 m] −2 . The prevalence of ACR <1.1 mg/mmol was lower but still significant (34.5%) in those with stage ≥3 CKD. In logistic regression analysis, stages 1–2 and ≥3 CKD were independently associated with age, HbA 1c , γ-glutamyltransferase, fibrinogen, hypertension, but not with sex, BMI, smoking, HDL-cholesterol or triacylglycerol. Inclusion of advanced retinopathy removed HbA 1c from the model. The CKD Alb + phenotype correlated with diabetes duration, HbA 1c , HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb − phenotype was associated with age and hypertension, but not with diabetes duration, HbA 1c and fibrinogen. Conclusions/interpretation The Alb − CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb + and Alb − ) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes.

This study aimed to evaluate the clinical benefits of incorporating a widefield lens (WFL) in optical coherence tomography angiography (OCT-A) in patients with retinal vascular diseases in comparison to standard single-shot OCT-A scans. Sixty patients with retinal vascular diseases including diabetic retinopathy (DR) and retinal vein occlusion (RVO) were recruited. OCT-A imaging (PlexElite 9000) with and without WFL was performed in randomized order. The assessment included patient comfort, time, field of view (FoV), image quality and pathology detection. Statistical analysis included paired t -tests, Mann–Whitney U -tests and Bonferroni correction for multiple tests, with inter-grader agreement using the kappa coefficient. Using a WFL did not lead to statistically significant differences in DR and RVO group test times. Patient comfort remained high, with similar responses for WFL and non-WFL measurements. The WFL notably expanded the scan field (1.6× FoV increase), enhancing peripheral retinal visibility. However, image quality varied due to pathology and eye dominance, affecting the detection of peripheral issues in RVO and DR cases. The use of a WFL widens the scan field, aiding vascular retinal disease imaging with minor effects on comfort, time, and image quality. Further enhancements are needed for broader view angles, enabling improved quantification of non-perfused areas and more reliable peripheral proliferation detection.

The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. During 10 years of follow-up, HbA(1c) (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%). Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

Aims/hypothesis The aim of the present study was to investigate the effect of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in type 2 diabetic patients. Methods The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Retinal Measurements study, a substudy of ADVANCE, is a randomised (using a central, computer-based procedure) controlled 2 x 2 factorial trial comprising a double-blind comparison of blood pressure lowering with perindopril-indapamide vs placebo, and an open comparison of standard vs intensive glucose control targeting a HbA₁c of <= 6.5% in 1,602 diabetic patients from ADVANCE centres with access to retinal cameras conducted from 2001 to 2008. At baseline and the final visit, seven-field stereoscopic retinal photographs were taken and graded by blinded readers (gradeable baseline and final photographs from 1,241 patients). Progression of >=2 steps in the Early Treatment of Diabetic Retinopathy Study classification (using the eye with worst grading) was the primary outcome. Results Retinopathy progressed in 59 (4.8%) patients and developed in 128 (10.3%) patients over 4.1 years. Fewer patients on blood pressure-lowering treatment (n = 623) experienced incidence or progression of retinopathy compared with patients on placebo (n = 618), but the difference was not significant (OR 0.78; 95% CI 0.57-1.06; p = 0.12). Blood pressure-lowering treatment reduced the occurrence of macular oedema (OR 0.50; 95% CI 0.29-0.88; p = 0.016) and arteriovenous nicking compared with placebo (OR 0.60; 95% CI 0.38-0.94; p = 0.025). Compared with standard glucose control (n = 611), intensive glucose control (n = 630) did not reduce (p = 0.27) the incidence and progression of retinopathy (OR 0.84; 95% CI 0.61-1.15). Lower, borderline significant risks of microaneurysms, hard exudates and macular oedema were observed with intensive glucose control, adjusted for baseline retinal haemorrhages. These effects of the two treatments were independent and additive. Adverse events in the ADVANCE study are reported elsewhere. Conclusions/interpretation Blood pressure lowering or intensive glucose control did not significantly reduce the incidence and progression of retinopathy, although consistent trends towards a benefit were observed, with significant reductions in some lesions observed with both interventions. Trial registration: ClinicalTrials.gov ID no. NCT00145925. Funding: Grants from Servier and the National Health and Medical Research Council of Australia

Aim:The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO).Methods:Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli–Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months.Results:All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001).Conclusion:Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO.Trial registration number:ISTRN 90646644.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes, and retinal microaneurysms (MA) are one of the first detected abnormalities associated with DR. We recently showed elevated serum triglyceride levels to be associated with the development of MA in the Finnish Diabetes Prevention Study (DPS). The purpose of this metabolomics study was to assess whether serum fatty acid (FA) composition, plasmalogens, and low-grade inflammation may enhance or decrease the risk of MA. Originally, the DPS included 522 individuals (mean 55 years old, range 40–64 years) with impaired glucose tolerance who were randomized into an intervention (n = 265) or control group (n = 257). The intervention lasted for a median of four years (active period), after which annual follow-up visits were conducted. At least five years after stopping the intervention phase of DPS, participants classified as MA negative (n = 115) or MA positive (n = 51) were included in the current study. All these participants were free of diabetes at baseline (WHO 1985) and had high-sensitive C-reactive protein (hs-CRP), serum FA composition, and selected lipid metabolites measured during the active study period. Among the markers associated with MA, the serum plasmalogen dm16:0 (p = 0.006), the saturated odd-chain FA 15.0 (pentadecanoic acid; p = 0.015), and omega-3 very long-chain FAs (p < 0.05) were associated with a decreased occurrence of MA. These associations were independent of study group and other risk factors. The association of high serum triglycerides with the MA occurrence was attenuated when these MA-associated serum lipid markers were considered. Our findings suggest that, in addition to n-3 FAs, odd-chain FA 15:0 and plasmalogen dm16:0 may contribute to a lower risk of MA in individuals with impaired glucose tolerance. These putative novel lipid biomarkers have an association with MA independently of triglyceride levels.

PurposeTo compare changes in retinal vascular calibre after 2 years of treatment with intravitreal bevacizumab (BVZ) or dexamethasone implant (DEX) in patients with centre-involving diabetic macular oedema (DMO).MethodsAt baseline, 88 eyes of 61 patients with DMO were recruited in a prospective, multicentre, randomised, single-masked clinical trial. Of these subjects, 22 BVZ-treated (52%) and 22 DEX-treated (48%) eyes of 34 patients (56%) had gradable retinal photographs at both the baseline and 24-month visits. Retinal vascular calibre was measured from digital fundus photographs and summarised as central retinal artery (CRAE) and vein (CRVE) equivalents in all gradable eyes at baseline and 24 months.ResultsAt 24 months, 40.9% of BVZ and 45.5% of DEX eyes gained 10 or more letters (p=0.77). There was concurrent reduction in mean central macular thickness, −157.7 μm in BVZ and −192.5 μm in DEX-treated eyes (p=0.40). DEX-treated eyes showed a statistically significant reduction in CRVE compared with BVZ-treated eyes, with a mean change from baseline of −31.78 to +4.34 µm, respectively (p<0.001). CRAE showed a non-statistically significant trend towards reduction over time in DEX-treated eyes compared with BVZ-treated eyes, with a mean change from baseline of −6.09 and +1.66, respectively (p=0.077).ConclusionsDEX had a significant narrowing effect on venular diameter in eyes with DMO not seen with BVZ. The changes in retinal vascular calibre suggest that these agents have a differing actions effects retinal vasculature and thereby suggest a potentially different mechanism of action on reducing DMO.Trial registration numberNCT01298076.