Different retinopathy phenotypes in type 2 diabetes predict retinopathy progression

Abstract Purpose To characterize the progression in retinopathy severity of different phenotypes of mild nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes. Design and methods Patients with type 2 diabetes and mild NPDR (ETDRS 20 or 35) were followed in a 5-year longitudinal study. Examinations, including color fundus photography (CFP) and optical coherence tomography (OCT and OCTA), were performed at baseline, 6 months and then annually. Phenotype classification was performed based on microaneurysm turnover (MAT, on CFP) and central retinal thickness (CRT, on OCT). Phenotype A is characterized by low MAT (< 6) and normal CRT; Phenotype B by low MAT (< 6) and increased CRT; and Phenotype C by higher MAT (≥ 6) with or without increased CRT. ETDRS grading of seven fields CFP was performed at the initial and last visits. Results Analysis of ETDRS grade step changes showed significant differences in diabetic retinopathy (DR) progression between the different phenotypes (p < 0.001). Of the 66 participants with phenotype A only 2 eyes (3%) presented 2-or-more-step worsening. None of the 50 participants characterized as phenotype B developed 2-step worsening, whereas 13 eyes (23.2%) characterized as phenotype C had 2-or-more-steps worsening. Phenotype C presents the higher risk for 2-or-more step worsening (OR: 15.94 95% CI: 3.45–73.71; p < 0.001) and higher sensitivity, correctly identifying 86.7% of cases at risk (AUC: 0.84 95% CI: 0.72–0.96; p < 0.001). Diabetic retinopathy severity progression was associated with HbA1c (p = 0.019), LDL levels (p = 0.043), and ocular factors as MAT (p = 0.010), MA formation rate (p = 0.014) and MA disappearance rate (p = 0.005). Capillary closure at 5-year follow-up, identified by lower vessel density (VD) on OCTA, was also associated with diabetic DR severity progression (p = 0.035). Conclusions Different DR phenotypes in type 2 diabetes show different risks of retinopathy progression. Phenotype C is associated with increased HbA1c values and presents a higher risk of a 2-or-more-step worsening of the ETDRS severity score.

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Retinopathy Phenotypes in Type 2 Diabetes with Different Risks for Macular Edema and Proliferative Retinopathy

Journal of Clinical Medicine ◽

10.3390/jcm9051433 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1433 ◽

Cited By ~ 3

Author(s):

Ines P. Marques ◽

Maria H. Madeira ◽

Ana L. Messias ◽

Torcato Santos ◽

António C-V. Martinho ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Macular Edema ◽

Odds Ratio ◽

Retinal Thickness ◽

Proliferative Retinopathy ◽

Clinically Significant Macular Edema ◽

Clinically Significant

Our group reported that three diabetic retinopathy (DR) phenotypes: A, characterized by low microaneurysm turnover (MAT < 6) and normal central retinal thickness (CRT); B, low MAT (<6) and increased CRT, and C, high MAT (≥6), present different risks for development of macular edema (DME) and proliferative retinopathy (PDR). To test these findings, 212 persons with type 2 diabetes (T2D) and mild nonproliferative retinopathy (NPDR), one eye per person, were followed for five years with annual visits. Of these, 172 completed the follow-up or developed an outcome: PDR or DME (considering both clinically significant macular edema (CSME) and center-involved macular edema (CIME)). Twenty-seven eyes (16%) developed either CSME (14), CIME (10), or PDR (4), with one eye developing both CSME and PDR. Phenotype A showed no association with development of vision-threatening complications. Seven eyes with phenotype B and three with phenotype C developed CIME. Phenotype C showed higher risk for CSME development, with 17.41 odds ratio (p = 0.010), compared with phenotypes A + B. All eyes that developed PDR were classified as phenotype C. Levels of HbA1c and triglycerides were increased in phenotype C (p < 0.001 and p = 0.018, respectively). In conclusion, phenotype C identifies eyes at higher risk for development of CSME and PDR, whereas phenotype A identifies eyes at very low risk for vision-threatening complications.

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Development and Progression of Diabetic Retinopathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study

10.2337/figshare.15183393.v1 ◽

2021 ◽

Author(s):

Rose Gubitosi-Klug ◽

Ingrid Libman ◽

Kimberly L. Drews ◽

Diane Uschner ◽

Barbara A. Blodi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Treatment Options ◽

Diabetes Duration ◽

Fundus Photography ◽

Dominant Factor ◽

Fundus Photographs ◽

Design And Methods

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial reported a 13.9% prevalence of diabetic retinopathy (DR) in youth with an average 4.9 ± 1.5 years of type 2 diabetes duration. After seven years of additional follow up, we report the risk factors for progression of DR in the TODAY cohort. Research Design and Methods: Retinal photographs (n = 517) were obtained in 2010-2011 and again in 2017-18 (n = 420) with seven standard stereoscopic field digital fundus photography. Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Three hundred sixty-seven patients with gradable fundus photographs in at least one eye at both assessments were included in analyses of progression of diabetic retinopathy, defined as an increase of three or more steps on the ETDRS scale. Results: With mean age of 25.4 ± 2.5 years and diabetes duration of 12.0 ± 1.5 years, participants had a 49% prevalence of any diabetic retinopathy. Prevalence by DR stage included: 39% very mild or mild non-proliferative diabetic retinopathy (NPDR); 6% moderate to severe NPDR; and 3.8% proliferative diabetic retinopathy. Compared with non-progressors, participants who progressed three or more steps had significantly lower BMI, higher HbA1c, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA1c was the dominant factor impacting DR progression. Conclusions: Poor glycemic control of youth-onset type 2 diabetes imparts a high risk for progression of DR, including advanced, sight-threatening disease by young adulthood.

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Development and Progression of Diabetic Retinopathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study

10.2337/figshare.15183393 ◽

2021 ◽

Author(s):

Rose Gubitosi-Klug ◽

Ingrid Libman ◽

Kimberly L. Drews ◽

Diane Uschner ◽

Barbara A. Blodi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Treatment Options ◽

Diabetes Duration ◽

Fundus Photography ◽

Dominant Factor ◽

Fundus Photographs ◽

Design And Methods

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Profibrotic circulating proteins and risk of early progressive renal decline in Type 2 Diabetes patients with and without albuminuria

10.2337/figshare.12808433.v1 ◽

2020 ◽

Author(s):

Katsuhito Ihara ◽

Jan Skupien ◽

Hiroki Kobayashi ◽

Zaipul I. Md Dom ◽

Jonathan M. Wilson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Core Domain ◽

Fibrotic Process ◽

Baseline Levels ◽

Design And Methods ◽

Circulating Levels ◽

Index Combination

OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m2 were followed for 6-12 years to ascertain fast early progressive renal decline defined as eGFR loss ≥5 ml/min/1.73m2/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline were 97 ml/min/1.73m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal decline increased with increasing baseline levels of WFDC2 (p <0.0001) and MMP-7 (p <0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the Fibrosis Index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (OR 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in development of early renal decline.

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Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz069 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1549-e1560 ◽

Cited By ~ 7

Author(s):

Bénédicte Gaborit ◽

Jean-Baptiste Julla ◽

Samaher Besbes ◽

Matthieu Proust ◽

Clara Vincentelli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Fundus Photography ◽

Endothelial Cell Proliferation ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract 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.

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Correlation between markers of renal function and sight-threatening diabetic retinopathy in type 2 diabetes: a longitudinal study in an Indian clinic population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001325 ◽

Cited By ~ 1

Author(s):

Ramachandran Rajalakshmi ◽

Coimbatore Subramanian Shanthi Rani ◽

Ulagamathesan Venkatesan ◽

Ranjit Unnikrishnan ◽

Ranjit Mohan Anjana ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Serum Creatinine ◽

Cox Regression ◽

Tertiary Care ◽

Cox Regression Analysis ◽

Increased Risk ◽

New Onset

IntroductionPrevious epidemiological studies have reported on the prevalence of diabetic kidney disease (DKD) and diabetic retinopathy (DR) from India. The aim of this study is to evaluate the effect of DKD on the development of new-onset DR and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2D).Research design and methodsThe study was done on anonymized electronic medical record data of people with T2D who had undergone screening for DR and renal work-up as part of routine follow-up at a tertiary care diabetes center in Chennai, South India. The baseline data retrieved included clinical and biochemical parameters including renal profiles (serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria). Grading of DR was performed using the modified Early Treatment Diabetic Retinopathy Study grading system. STDR was defined as the presence of proliferative diabetic retinopathy (PDR) and/or diabetic macular edema. DKD was defined by the presence of albuminuria (≥30 µg/mg) and/or reduction in eGFR (<60 mL/min/1.73 m2). Cox regression analysis was used to evaluate the hazard ratio (HR) for DR and STDR.ResultsData of 19 909 individuals with T2D (mean age 59.6±10.2 years, mean duration of diabetes 11.1±12.1 years, 66.1% male) were analyzed. At baseline, DR was present in 7818 individuals (39.3%), of whom 2249 (11.3%) had STDR. During the mean follow-up period of 3.9±1.9 years, 2140 (17.7%) developed new-onset DR and 980 individuals with non-proliferative DR (NPDR) at baseline progressed to STDR. Higher serum creatinine (HR 1.5, 95% CI 1.3 to 1.7; p<0.0001), eGFR <30 mL/min/1.73 m2 (HR 4.9, 95% CI 2.9 to 8.2; p<0.0001) and presence of macroalbuminuria >300 µg/mg (HR 3.0, 95% CI 2.4 to 3.8; p<0.0001) at baseline were associated with increased risk of progression to STDR.ConclusionsDKD at baseline is a risk factor for progression to STDR. Physicians should promptly refer their patients with DKD to ophthalmologists for timely detection and management of STDR.

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Thickness of Intraretinal Layers in Patients with Type 2 Diabetes Mellitus Depending on a Concomitant Diabetic Neuropathy: Results of a Cross-Sectional Study Using Deviation Maps for OCT Data Analysis

Biomedicines ◽

10.3390/biomedicines8070190 ◽

2020 ◽

Vol 8 (7) ◽

pp. 190

Author(s):

Ruby Kala Prakasam ◽

Aleksandra Matuszewska-Iwanicka ◽

Dagmar-Christiane Fischer ◽

Heidrun Schumann ◽

Diethelm Tschöpe ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Diabetic Retinopathy ◽

Retinal Thickness ◽

Early Stage ◽

Cross Sectional Study ◽

Cross Sectional ◽

Retinal Layers

Optical coherence tomography (OCT) supports the detection of thickness changes in intraretinal layers at an early stage of diabetes mellitus. However, the analysis of OCT data in cross-sectional studies is complex and time-consuming. We introduce an enhanced deviation map-based analysis (MA) and demonstrate its effectiveness in detecting early changes in intraretinal layer thickness in adults with type 2 diabetes mellitus (T2DM) compared to common early treatment diabetic retinopathy study (ETDRS) grid-based analysis (GA). To this end, we obtained OCT scans of unilateral eyes from 33 T2DM patients without diabetic retinopathy and 40 healthy controls. The patients were categorized according to concomitant diabetic peripheral neuropathy (DN). The results of MA and GA demonstrated statistically significant differences in retinal thickness between patients and controls. Thinning was most pronounced in total retinal thickness and the thickness of the inner retinal layers in areas of the inner macular ring, selectively extending into areas of the outer macular ring and foveal center. Patients with clinically proven DN showed the strongest thinning of the inner retinal layers. MA showed additional areas of thinning whereas GA tended to underestimate thickness changes, especially in areas with localized thinning. We conclude that MA enables a precise analysis of retinal thickness data and contributes to the understanding of localized changes in intraretinal layers in adults with T2DM.

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Diabetic Retinopathy Grade as a Predictive Marker of Stroke and Mortality in Type 2 Diabetes Mellitus Patients with Amputations—Seven-Year Follow-Up

Diabetes ◽

10.2337/db18-603-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 603-P

Author(s):

KIRAN SHAH ◽

NATARAJAN SUNDARAM ◽

ABHAY A. RAUT ◽

KARTHIK RAO ◽

NAVNEET WADHWA

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Diabetic Retinopathy ◽

Predictive Marker

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Relationship between diabetic retinopathy stages and risk of major lower-extremity arterial disease in patients with type 2 diabetes

10.2337/figshare.12777407.v1 ◽

2020 ◽

Author(s):

Ninon Foussard ◽

Pierre-Jean Saulnier ◽

Louis Potier ◽

Stéphanie Ragot ◽

Fabrice Schneider ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Lower Extremity ◽

Incidence Rate ◽

Cox Regression ◽

Arterial Disease ◽

Lower Extremity Arterial Disease ◽

C Statistic

Objective. We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors in this relationship in a prospective cohort of patients with type 2 diabetes. Research design and methods. Diabetic retinopathy was staged at baseline as absent, non-proliferative or proliferative. Cox regression model was fitted to compute HR (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. Retinopathy-LEAD association was assessed in subgroups by age, gender, diabetes duration, HbA1c, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy to stratify LEAD risk was assessed using c-statistic, integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Results. Among 1320 participants without a baseline history of LEAD, 94 (7.1%) patients developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6, 95%CI [7.8–11.7] per 1000 person-years). The LEAD incidence rate increased by worsening retinopathy: absent 5.5 (3.9–7.8), non-proliferative 14.6 (11.1–19.3), proliferative 20.1 (11.1–36.3) per 1000 person-years. Compared with absent retinopathy, non-proliferative (multi-adjusted HR 2.31, 95%CI [1.43–3.81], p=0.0006) and proliferative retinopathy (3.14 [1.40–6.15], p=0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced c-statistic (+0.023 [0.003–0.044], p=0.02), IDI (0.209 [0.130 – 0.321], p<0.001) and NRI (0.562 [0.382– 0.799], p<0.001) for LEAD risk, beyond traditional risk factors. Conclusions. An independent dose-response relationship was observed between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for LEAD risk stratification, suggesting its usefulness as LEAD predictor.

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Assessing the changes in eye optics and visual functions in patients with insulin-dependent type 2 diabetes mellitus and their relationship with blood glucose level

Russian Ophthalmological Journal ◽

10.21516/2072-0076-2018-11-4-5-13 ◽

2018 ◽

Vol 11 (4) ◽

pp. 5-13

Author(s):

L. A. Mineeva ◽

L. I. Balashevich ◽

A. A. Baranov ◽

L. B. Shubin ◽

A. V. Kabanov

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Blood Glucose ◽

Insulin Therapy ◽

Glucose Level ◽

Glycated Hemoglobin ◽

Insulin Dependent

Purpose: To assess the changes in eye optics and visual functions depending on the level of blood sugar and glycated hemoglobin (HbA1c) in insulin-dependent type 2 diabetes mellitus (IPSD) patients with excessive body weight, who receive long-term insulin therapy.Material and methods. 32 patients (64 eyes), of which 84.4 % were women and 15.6 % men, with insulin-dependent diabetes mellitus (IPSD) but without severe general diabetic complications or concomitant eye pathology were monitored ophthalmologically for 3 years. The average duration of insulin therapy was 6 years. The average age of the patients was 60.94 ± 1.04 years; average weight, 89.1 ± 14.8 kg; average height, 163.8 ± 7.3 cm; average body mass index, 31.3 ± 4.8 kg/m2. The level of blood glucose level was determined daily with individual Accu-Check and/or OneTouch select glucometers, supplemented by scheduled monthly examinations with an endocrinologist. The level of glycated hemoglobin (HbA1c) was determined once every 3–6 months. Vision was measured by international requirements for patients with diabetes using the ETDRS (Early Treatment Diabetic Retinopathy Study Research Group) system with an ESV-3000 device. To assess lens transparency, the international Lens Opacities Classification System III (LOCS III) was used. Glycaemia level was monitored by the patients themselves with the help of individual blood glucose meters and by endocrinologists in scheduled monthly checkups. HbA1c level was measured once every 3 to 6 months.Results. Over the follow-up period, the subjective visual acuity slightly deteriorated. The anterior segment remained practically unchanged, the vitreous body showed a destruction increase, the state of the retina remained stable and conformed to that of nonproliferative diabetic retinopathy. The glucose level showed a significant drop, while the level of glycated hemoglobin HbA1c practically remained constant. The LOCS III criteria showed an increased clarity of the lens nucleus (NO), a worse transparency of cortical layers (C) deteriorated; the NC nucleus colour and P parameters of the posterior subcapsular layer practically remained the same. Conclusions. According to our data, during the development of diabetic cataracts in patients with type 2 IPSD, NO of the lens changes first followed by C changes (they become worse). With the normalization of glycemia level, diabetic retinopathy does not progress, the NO of the lens can improve, and the NC and P do not change. Normalization of glycemia is not a retarding factor for the already existing changes in C or the state of the vitreous. HbA1c is a marker and trigger for possible lens changes in patients with type 2 diabetes and prolonged insulin therapy. HbA1с is effective for tracking the dynamics of changes in the eye in these patients. The fact that the positive correlation of HbA1c and C at follow-up start changed to the negative correlation toward the end of the study indicates a disruption in lens state compensation and does not cancel the negative dynamics of state C even with a decrease in the level of HbA1c.

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