Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME CI-DME) with ...visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown.
To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation.
Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018.
Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits.
The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported.
Among 702 randomized participants (mean age, 59 years; 38% female n=264), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% 95% CI, -9% to 5%; relative risk, 0.88 95% CI, 0.57-1.35; P = .79; aflibercept vs observation risk difference, -3% 95% CI, -11% to 4%; relative risk, 0.83 95% CI, 0.55-1.27; P = .79; laser photocoagulation vs observation risk difference, -1% 95% CI, -9% to 6%; relative risk, 0.95 95% CI, 0.64-1.41; P = .79). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups.
Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME.
ClinicalTrials.gov Identifier: NCT01909791.
Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In
mice, we examined the ...impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin,
mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with
mice on ad libitum feeding, changes in the microbiome of the
mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in
on IF but not in
on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.
Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied ...for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors (‘anti-VEGFs’) and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure.
This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.
Diabetic retinopathy remains the most common complication of diabetes mellitus and is a leading cause of visual loss in industrialized nations. The clinicopathology of the diabetic retina has been ...extensively studied, although the precise pathogenesis and cellular and molecular defects that lead to retinal vascular, neural and glial cell dysfunction remain somewhat elusive. This lack of understanding has seriously limited the therapeutic options available for the ophthalmologist and there is a need to identify the definitive pathways that initiate retinal cell damage and drive progression to overt retinopathy. The present review begins by outlining the natural history of diabetic retinopathy, the clinical features and risk factors. Reviewing the histopathological data from clinical specimens and animal models, the recent paradigm that neuroretinal dysfunction may play an important role in the early development of the disease is discussed. The review then focuses on the molecular pathogenesis of diabetic retinopathy with perspective provided on new advances that have furthered our understanding of the key mechanisms underlying early changes in the diabetic retina. Studies have also emerged in the past year suggesting that defective repair of injured retinal vessels by endothelial progenitor cells may contribute to the pathogenesis of diabetic retinopathy. We assess these findings and discuss how they could eventually lead to new therapeutic options for diabetic retinopathy.
Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed.
To evaluate efficacy and safety of 0.5-mg ...intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR.
Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018.
Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group.
Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety.
The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified.
Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR.
ClinicalTrials.gov Identifier: NCT01489189.
Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes ...mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced “type 1” and B6.BKS(D)-Leprdb/J “type 2” diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.
Diabetic retinopathy remains as a leading cause of blindness in developed countries. Current treatments target late stages of DR when vision has already been significantly affected. A better ...understanding of the pathogenesis of DR would permit the development of more efficient preventional/interventional strategies against early stages of DR. In this article a critical review of the state of the art of this issue is provided along with a discussion of problems which have yet to be overcome. Neuroprotection as a new approach for the treatment of the early stages of DR has been particularly emphasized.
The development and progression of DR is not homogeneous and, apart from blood glucose levels and blood pressure, it depends on genetic factors which remain to be elucidated. In addition, the role of the pathogenic pathways is not the same in all patients. All these factors should be taken into account in the near future when an individualized oriented treatment for DR could become feasible. The new techniques in retinal imaging acquisition, the identification of useful circulating biomarkers and the individualized analysis of biological samples could facilitate the development of early and personalized therapy in the setting of DR.
Finally, it should be noted that only a coordinated action among ophthalmologists, diabetologists, basic researchers, experts in pharmaco-economics and health care providers addressed to the design of rational strategies targeting prevention and the early stages of DR will be effective in reducing the burden and improving the clinical outcome of this devastating complication of diabetes.
To quantify changes in retinal microvasculature in diabetic retinopathy (DR) by using spectral-domain optical coherence tomography angiography (SD-OCTA).
Retrospective, cross-sectional, observational ...study of healthy and diabetic adult subjects with and without DR. Retinal microvascular changes were assessed by using SD-OCTA images and an intensity-based optical microangiography algorithm. A semiautomated program was used to calculate indices of microvascular density and morphology in nonsegmented and segmented SD-OCTA images. Microvascular density was quantified by using skeleton density (SD) and vessel density (VD), while vessel morphology was quantified as fractal dimension (FD) and vessel diameter index (VDI). Statistical analyses were performed by using the Student's t-test or analysis of variance with post hoc Tukey honest significant difference tests for multiple comparisons.
Eighty-four eyes with DR and 14 healthy eyes were studied. Spearman's rank test demonstrated a negative correlation between DR severity and SD, VD, and FD, and a positive correlation with VDI (ρ = -0.767, -0.7166, -0.768, and +0.5051, respectively; P < 0.0001). All parameters showed high reproducibility between graders (ICC = 0.971, 0.962, 0.937, and 0.994 for SD, VD, FD, and VDI, respectively). Repeatability (κ) was greater than 0.99 for SD, VD, FD, and VDI.
Vascular changes in DR can be objectively and reliably characterized with SD, VD, FD, and VDI. In general, decreasing capillary density (SD and VD), branching complexity (FD), and increasing average vascular caliber (VDI) were associated with worsening DR. Changes in capillary density and morphology were significantly correlated with diabetic macular edema.
Diabetic Retinopathy Hendrick, Andrew M; Gibson, Maria V; Kulshreshtha, Ambar
Primary care,
09/2015, Volume:
42, Issue:
3
Journal Article
Peer reviewed
The prevalence of diabetes is on the rise globally as are the consequences, such as diabetic retinopathy. Diabetic retinopathy is a leading cause of vision loss in working-age adults in developed ...countries. Visual impairment as a result of diabetic retinopathy has a significant negative impact on the patient's quality of life and their ability to successfully manage their disease. Glycemic control, blood pressure normalization, and lipid management form the basis for long-term diabetes management and protection from worsening eye disease.
Diabetic retinopathy is a multifactorial disease, and the exact mechanism of its pathogenesis remains obscure. Sirtuin 1 (Sirt1), a multifunctional deacetylase, is implicated in the regulation of ...many cellular functions and in gene transcription, and retinal Sirt1 is inhibited in diabetes. Our aim was to determine the role of Sirt1 in the development of diabetic retinopathy and to elucidate the molecular mechanism of its downregulation. Using
-overexpressing mice that were diabetic for 8 months, structural, functional, and metabolic abnormalities were investigated in vascular and neuronal retina. The role of epigenetics in
transcriptional suppression was investigated in retinal microvessels. Compared with diabetic wild-type mice, retinal vasculature from diabetic
mice did not present any increase in the number of apoptotic cells or degenerative capillaries or decrease in vascular density. Diabetic
mice were also protected from mitochondrial damage and had normal electroretinography responses and ganglion cell layer thickness. Diabetic wild-type mice had hypermethylated
promoter DNA, which was alleviated in diabetic
mice, suggesting a role for epigenetics in its transcriptional suppression. Thus strategies targeted to ameliorate Sirt1 inhibition have the potential to maintain retinal vascular and neuronal homeostasis, providing opportunities to retard the development of diabetic retinopathy in its early stages.
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