Early Worsening Of Diabetic Retinopathy Research Articles

Intensive glucose control and the clinical paradox of transient progression of diabetic retinopathy: Prioritising the relevance of eye screening intervals.

The paradoxical early worsening of diabetic retinopathy with optimisation of glycaemic control is well recognised. Patients with type 2 diabetes mellitus with R0M0 grading at eye screening with enhanced glycaemic control and progression of diabetic retinopathy may get missed with just biennial monitoring as per the changes to national diabetes eye screening programme guidelines. However, from the perspective of patients with type 1 diabetes mellitus being offered newer hybrid closed-loop systems for insulin delivery, very recent guidance allows for this recommendation of a 24-month screening interval to be adjusted. There is an override option within the screening software to enable an additional 12-month screen following the initiation of the closed-loop system. More frequent screening during pregnancy when glycaemic control is tightened, was established several years ago. Interestingly, no such guidance is currently available for patients being treated with GLP-1RA for T2DM, or in patients following bariatric surgery despite the well-recognised impact that has been observed. With newer incretin mimetic treatments in the horizon, this warrants a review and needs a re-appraisal.

Rapid Reduction of HbA1c and Early Worsening of Diabetic Retinopathy: A Real-world Population-Based Study in Subjects With Type 2 Diabetes.

Early worsening of diabetic retinopathy (EWDR) due to the rapid decrease of blood glucose levels is a concern in diabetes treatment. The aim of the current study is to evaluate whether this is an important issue in subjects with type 2 diabetes with mild or moderate nonproliferative DR (NPDR), who represent the vast majority of subjects with DR attended in primary care. This is a retrospective nested case-control study of subjects with type 2 diabetes and previous mild or moderate NPDR. Using the SIDIAP ("Sistema d'informació pel Desenvolupament de la Recerca a Atenció Primària") database, we selected 1,150 individuals with EWDR and 1,150 matched control subjects (DR without EWDR). The main variable analyzed was the magnitude of the reduction of HbA1c in the previous 12 months. The reduction of HbA1c was categorized as rapid (>1.5% reduction in <12 months) or very rapid (>2% in <6 months). We did not find any significant difference in HbA1c reduction between case and control subjects (0.13 ± 1.21 vs. 0.21 ± 1.18; P = 0.12). HbA1c reduction did not show significant association with worsening of DR, neither in the unadjusted analyses nor in adjusted statistical models that included the main confounding variables: duration of diabetes, baseline HbA1c, presence of hypertension, and antidiabetic drugs. In addition, when stratification by baseline HbA1c was performed, we did not find that those patients with higher levels of HbA1c presented a higher risk to EWDR. Our results suggest that the rapid reduction of HbA1c is not associated with progression of mild or moderate NPDR.

Bariatric surgery in individuals with type 2 diabetes is not associated with short or long-term risk of diabetic retinopathy progression: results from a nationwide cohort study.

Bariatric surgery is used to induce weight loss and glycemic stability in type 2 diabetes (T2D). It has been a concern that this may lead to early worsening of diabetic retinopathy (DR) due to a rapid decline in HbA1c. In this study, we evaluated the risk of short and long-term DR development and need for ocular intervention in an entire nation of individuals with T2D undergoing bariatric surgery. The study comprised a national, register-based cohort of individuals with T2D screened for DR. Cases were matched by age, sex and DR level at the date of surgery (index date) with non-bariatric controls. We extracted information on DR levels, in- and outpatient treatments, pharmaceutical prescriptions and laboratory values. We evaluated worsening of DR (incident and progressive DR) at follow-up (6 and 36months). Amongst 238,967 individuals with T2D, who attended diabetic eye screening, we identified 553 that underwent bariatric surgery (0.2%) and 2677 non-bariatric controls. Median age was 49years, and 63% were female. Cases had more comorbidities, lower HbA1c as well as more frequent use of glucose-lowering and antihypertensive medication than controls at index date. In a fully adjusted logistic regression model, the risk of DR worsening for cases was not significantly different compared to controls, neither short-term (OR 0.41 [CI 95% 0.13; 1.33], p = 0.14) nor long-term (OR 0.64 [CI 95% 0.33; 1.24], p = 0.18). In this nationwide study, bariatric surgery did not associate with increased risk of short- or long-term DR worsening.

Early Worsening of Retinopathy in Type1 and Type2 Diabetes After Rapid Improvement in Glycaemic Control: A Systematic Review.

To systematically review the epidemiology of early worsening of diabetic retinopathy (EWDR) after substantial improvements in glycaemic control and evaluate characteristics including risk factors. This systematic review was registered with PROSPERO (CRD42020158252). An electronic literature search was performed according to PRISMA guidelines using MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Cochrane databases and manual reference for the articles published until 2020. Published full-text English language articles that report data on diabetic retinopathy in people with diabetes experiencing a rapid, substantial decrease in HbA1c after going through intensive therapy were included. All articles were screened, data were extracted and methodological quality was evaluated by two independent reviewers using a priori criteria. A total of 346 articles were identified after the removal of duplicates. Data were extracted from 19 full-text articles with a total of 15,588 participants. Included studies varied considerably in terms of patient selection, timing and method of assessing the eye and retinopathy classification. EWDR was reported to occur in a wide range of prevalences; 3.3–47% of participants within 3–84 months after intensification of glycaemic control. Risk factors for EWDR included long duration of diabetes, long-term uncontrolled hyperglycemia, amplitude of and baseline retinopathy severity in both type 1 and type 2 diabetes. The occurrence of EWDR and progression of retinopathy were found to have an association with the amplitude of HbA1c reduction. EWDR has been described in a proportion of people with intensification of glycaemic control. However, the prevalence remains unclear because of methodological differences in the identified studies. Future interventional studies should report retinopathy and visual outcomes using standardized protocols.

Characteristics Associated with Early Worsening of Retinopathy in Patients with Type 2 Diabetes Diagnosed with Retinopathy at Their First Visit: A Retrospective Observational Study.

Materials and Methods Our study design was a retrospective observational study. Subjects with type 2 diabetes diagnosed with either simple or preproliferative diabetic retinopathy by ophthalmologists at their first visit and followed up for 6–18 months thereafter were included and divided into worsening and nonworsening groups. Thereafter, baseline characteristics and changes in HbA1c and therapy over a year were investigated. Results Among the 88 subjects with simple diabetic retinopathy, 16% improved to no retinopathy, 65% retained their simple diabetic retinopathy, 18% worsened to preproliferative diabetic retinopathy, and 1% worsened to proliferative diabetic retinopathy. Among the 47 subjects with preproliferative diabetic retinopathy, 9% improved to simple diabetic retinopathy, 72% retained their preproliferative diabetic retinopathy, and 19% worsened to proliferative diabetic retinopathy. Patients with simple diabetic retinopathy had an odds ratio of 1.44 for worsening retinopathy with a 1% increase in baseline HbA1c. Meanwhile, the odds ratios for worsening retinopathy with a 1% decrease in HbA1c from baseline at 3, 6, and 12 months were 1.34, 1.31, and 1.38, respectively. Among patients with simple diabetic retinopathy, significantly more new interventions were introduced in the worsening group than in the nonworsening group. Conclusions Increased baseline HbA1c, a substantial decrease in HbA1c, and intensified therapy were identified as risk factors for early worsening of diabetic retinopathy in patients with simple diabetic retinopathy at the first visit. Patients should therefore be intimately followed for retinopathy after their first visit.

Management of Patients with Newly Diagnosed Diabetic Mellitus: Ophthalmologic Outcomes in Intensive versus Conventional Glycemic Control.

Background and ObjectiveDiabetic retinopathy, a microvascular complication of diabetes mellitus, is one of the most important causes of visual loss in developed countries. Our objective is to evaluate the efficacy of intensive versus conventional glycemic control of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients in terms of ophthalmologic outcome, pathogenesis of the early worsening of diabetic retinopathy, risk factors for early worsening and diabetic retinopathy progression.MethodsA literature search on publications concerning glycaemic control in diabetic retinopathy and management of newly diagnosed diabetes mellitus by intensive versus conventional glycaemic control.ResultsA total of 22 articles were reviewed after curation by the authors for relevance. Nineteen articles are randomized control trial, 2 articles are observational studies and 1 is clinical trial. Fifteen articles investigated the glycaemic control in T1DM-related diabetic retinopathy and 8 on T2DM-related diabetic retinopathy. The level of glycemia (in terms of HbA1c level) is significantly related to the diabetic retinopathy progression in both T1DM and T2DM. Intensive glycemic control was found to reduce the development of severe diabetic retinopathy, including severe non-proliferative diabetic retinopathy, neovascularization, clinically significant macular edema and loss of vision. Early worsening of diabetic retinopathy commonly occurs during the first year of intensive treatment, especially those initially present with proliferative or severe non-proliferative retinopathy. However, most patients with early worsening can recover and their long-term ophthalmologic outcomes are better when compared to conventional glycemic control.ConclusionThe current guideline on HbA1c level is considered sufficient for the minimization of diabetic retinopathy progression. More frequent monitoring for early worsening should be recommended for newly diagnosed diabetes cases already presenting with retinopathy.

Substantial HbA1c Reduction Following Intermittent-Scanning Continuous Glucose Monitoring Was Not Associated With Early Worsening of Retinopathy in Type 1 Diabetes.

Early worsening of diabetic retinopathy (EWDR) was observed in the intensively treated arm of the Diabetes Control and Complications Trial (DCCT) before long-term benefits accrued. We sought to assess whether there may be an increased risk of EWDR in high-risk individuals following intermittent-scanning continuous glucose monitoring (iscCGM) commencement. An observational study of 139 individuals with type 1 diabetes ≥5 years duration and with baseline HbA1c >75 mmol/mol (9.0%). This cohort was stratified by subsequent HbA1c response to iscCGM (best responders and non-responders). Pan-retinal photocoagulation (PRP), worsening retinopathy status and new development of retinopathy were compared between groups. HbA1c change was -23 mmol/mol (IQR -32 to -19) (-2.1% [-2.9 to -1.8]) in responders and +6 mmol/mol (2-12) (+0.6 [0.2-1.1]) in non-responders (P < .001). There was no difference in subsequent PRP between responders (14.1%) and non-responders (10.3%, P = .340). Baseline HbA1c (HR 1.052 per mmol/mol, P = .002) but not response category (HR 1.244, P = .664) was independently associated with the risk of requiring PRP. Worsening of retinopathy was not different between responders (16.9%) and non-responders (20.6%, P = .577), and the same was true with respect to new development of retinopathy (33.3% vs 31.8%, P = .919). In a cohort enriched for risk of diabetic retinopathy, reduction in HbA1c did not result in an increased risk of PRP, worsening retinopathy, or new development of retinopathy. These findings offer reassurance that substantial reduction in HbA1c is not independently associated with early worsening of diabetic eye disease in iscCGM users.

RAPID MACULAR CAPILLARY LOSS IN PATIENTS WITH UNCONTROLLED TYPE 1 DIABETES.

To analyze the evolution of macular vessel density (VD) over 1 year, during early worsening of diabetic retinopathy, in patients with uncontrolled Type 1 diabetes (T1D). Retrospective study of 12 eyes of 9 patients with T1D with early worsening of diabetic retinopathy imaged with optical coherence tomography angiography. The following data were collected at the time of pan retinal photocoagulation initiation and after 6 and 12 months: vessel density within three retinal plexuses-superficial vascular plexus, intermediate capillary plexus, and deep capillary plexus; foveal avascular zone area, acircularity index, and flow density (FD)-300; central macular thickness; and HbA1c levels. A history of rapid reduction in blood glucose was found in seven of nine cases. Vessel density was significantly decreased at 12 months in all plexuses: from 44.68 ± 4.75 to 40.23 ± 7.13 in the superficial vascular plexus (P = 0.008), from 42.72 ± 4.86 to 37.12 ± 8.64 in the intermediate capillary plexus (P = 0.03), and from 22.68 ± 3.93 to 19.66 ± 4.92 in the deep capillary plexus (P = 0.004). Intermediate capillary plexus and deep capillary plexus changes were strongly correlated (r = 0.86, P < 0.001) and were significant as early as 6 months. The mean foveal avascular zone area increased (P = 0.05) and the FD-300 decreased (P = 0.03). No significant change in acircularity index, central macular thickness, and visual acuity were observed over time. Early worsening of diabetic retinopathy induces a rapid macular capillary dropout mainly affecting the intermediate capillary plexus and deep capillary plexus.

Early worsening of diabetic retinopathy after simultaneous pancreas and kidney transplantation-Myth or reality?

Early worsening of diabetic retinopathy due to sudden glucose normalization is a feared complication of pancreas transplantation; however, its rate or severity has not been studied prospectively. We followed up 43 pancreas and kidney recipients for a composite endpoint comprising new need for laser therapy, newly diagnosed proliferation, macular edema, visual acuity worsening, and blindness over 12months. Although 37% of patients met this primary endpoint, its severity was rather low. Mean central retinal thickness and proportion of patients with subclinical macular edema increased significantly, with spontaneous resolution in half of them. Visual acuity did not change. There was no significant difference in the absolute glycated hemoglobin (HbA1c) drop, age, and diabetes duration between the patients who met and those who did not meet the primary endpoint, but a higher proportion of patients with worsening had a recent history of laser treatment. Retinopathy remained stable in 62.8% of patients. In 26%, the visual acuity significantly improved. Although retinopathy worsening was documented in more than one-third of patients, its evolution was not related to the magnitude of metabolic change; rather, it corresponded to the expected natural course of retinopathy. Nonetheless, comprehensive ophthalmologic care should be a substantial component of the recipient management.

Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.

AimsTo evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.Materials and methodsThe SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon‐like peptide‐1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2‐year, pre‐approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at‐risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage‐points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.ResultsThere was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre‐existing DR and poor glycaemic control at baseline, and who were treated with insulin.ConclusionsEarly worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Early Retinopathy Progression in Four Randomized Trials Comparing Insulin Glargine and Nph Insulin

Early worsening of diabetic retinopathy, characterized by cotton wool spots, intraretinal microvascular abnormalities and/or macular edema, can occur following improvement of glycemic control. In four randomized 28- to 52-week clinical trials comparing insulin glargine and NPH insulin in regard to glycemic control and frequency of hypoglycemia, ophthalmologic examinations and fundus photographs were included to assess frequency of early worsening of retinopathy or other early adverse ocular effects. Retinopathy progression rates at 28 weeks were 7-12% by clinical examination and 3-8% by photographic grading; corresponding rates of clinically significant macular edema (CSME) were 1-8% and 1-4%, respectively. Optic disc swelling was not observed clinically or in photographs. Two of the 24 possible comparisons (four trials, three outcomes, two assessment methods), both of which were photographic assessments in type 2 diabetes, were in/near the nominally significant range and favored NPH insulin: 28-week rates of >or=3-step retinopathy progression (insulin glargine: 16/213, 7.5%; NPH insulin: 6/220, 2.7%; p=0.028) and 52-week CSME rates (26/233, 11.2% and 14/214, 6.5%, respectively; p=0.098). Because the between-treatment differences were small and inconsistent across trials and assessment methods, and because overall rates were consistent with the natural course of diabetic retinopathy, we conclude that it is unlikely that insulin glargine carries a higher risk of early worsening or other early adverse effect than NPH insulin. These trials tended to exclude a large early adverse effect, such as optic disc swelling, but cannot assess longer-term effects; a 5-year randomized trial of insulin glargine versus NPH insulin has been initiated. Data from this manuscript have been presented as posters and published in abstract form at the European Association for the Study of Diabetes 2001 ( DIABETOLOGIA 44(Suppl 1):I-IV(A287), 2001) and the Latin American Diabetes Association 2001 (11-15 November 2001, Punta del Este, Uruguay; Poster 180) congresses.

Diabetic Retinopathy: Unraveling the Paradoxical Effects of Intensive Insulin Treatment

Background:Several major clinical trials have demonstrated that the tight glycemic control achieved with intensive insulin treatment may lead to an early worsening of diabetic retinopathy but that intensive long-term insulin treatment slows the progression of diabetic retinopathy. Objective:The goal of this article was to review developments in understanding both the pathophysiologic pathways involved in diabetic retinopathy and the biologic effects of insulin to provide a possible explanation why insulin treatment may have deleterious short-term effects yet provide long-term benefits. Methods:The content of this article was based on a search of MEDLINE from 1984 through 2006. English-language articles were chosen using the search terms diabetic retinopathy, insulin effects, and clinical trials. Results: Early worsening of diabetic retinopathy from acute intensive insulin treatment may result from upregulation of retinal vascular endothelial growth factor (VEGF) expression through increased binding of hypoxia-inducible factorla to the VEGF promoter. This results in increased gene transcription and VEGF levels. Increased VEGF levels also promote activation of protein kinase C; both events contribute to increased vasopermeability and a breakdown of the blood-retinal barrier. However, long-term insulin treatment reduces inflammatory and oxidative stress components that may contribute to progressive diabetic retinopathy. Both inflammatory effects and oxidative stress may play a role in the etiology of diabetic retinopathy. The beneficial biologic effects of insulin may thus supercede the acute deleterious effects of the VEGF-mediated blood-retinal-barrier breakdown. We speculate that the long-term beneficial effects of intensive insulin therapy on the progression of diabetic retinopathy arise from insulin's recently realized potent anti-inflammatory effects and ability to modulate redox-sensitive signaling pathways. Conclusions:Insulin treatment introduced before irreversible pathologic changes develop in the retina can impart beneficial effects to the vascular cells, may help suppress future deleterious events, and may slow the development or progression of retinal microangiopathic changes.