Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

Vision is the most important sensory modality for many species, including humans. Damage to the retina results in vision loss or even blindness. One of the most serious complications of diabetes, a disease that has seen a worldwide increase in prevalence, is diabetic retinopathy. This condition stems from consequences of pathological metabolism and develops in 75% of patients with type 1 and 50% with type 2 diabetes. The development of novel protective drugs is essential. In this review we provide a description of the disease and conclude that type 1 diabetes and type 2 diabetes lead to the same retinopathy. We evaluate existing experimental models and recent developments in finding effective compounds against this disorder. In our opinion, the best models are the long-term streptozotocin-induced diabetes and Otsuka Long-Evans Tokushima Fatty and spontaneously diabetic Torii rats, while the most promising substances are topically administered somatostatin and pigment epithelium-derived factor analogs, antivasculogenic substances, and systemic antioxidants. Future drug development should focus on these

Intravitreal steroids for macular edema in diabetes

BACKGROUND: Diabetic macular edema (DME) is secondary to leakage from diseased retinal capillaries with thickening of central retina, and is an important cause of poor central visual acuity in people with diabetic retinopathy. Intravitreal steroids have been used to reduce retinal thickness and improve vision in people with DME. OBJECTIVES: To assess the effectiveness and safety of intravitreal steroid therapy compared with other treatments for DME. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on 15 May, 2019. We also searched reference lists, Science Citation Index, conference proceedings, and relevant trial registers. We conducted a top up search on 21 October, 2020. SELECTION CRITERIA: We included randomized controlled trials that evaluated any type of intravitreal steroids as monotherapy against any other intervention (e.g. observation, laser photocoagulation, anti‐vascular endothelial growth factor (antiVEGF) for DME. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and risk of bias and extracted data. Where appropriate, we performed meta‐analyses. MAIN RESULTS: We included 10 trials (4348 participants, 4505 eyes). These trials compared intravitreal steroid therapies versus other treatments, including intravitreal antiVEGF therapy, laser photocoagulation, and sham injection. Most trials had an overall unclear or high risk of bias. One trial (701 eyes ) compared intravitreal dexamethasone implant 0.7mg with sham. We found moderate‐certainty evidence that dexamethasone leads to slightly more improvement of visual acuity than sham at 12 months (mean difference [MD] −0.08 logMAR, 95% confidence interval [CI] −0.12 to −0.05 logMAR). Regarding improvement of three or more lines of visual acuity, there was moderate‐certainty evidence in favor of dexamethasone at 12 months, but the CI covered the null value (risk ratio (RR) 1.39, 95% CI 0.91 to 2.12). Regarding adverse events, dexamethasone increased by about four times the risk of cataract progression and the risk of using intraocular pressure (IOP)‐lowering medications compared to sham (RR 3.89, 95% CI 2.75 to 5.50 and RR 4.54, 95% CI 3.19 to 6.46, respectively; moderate‐certainty evidence); about 4 in 10 participants treated with dexamethasone needed IOP‐lowering medications. Two trials (451 eyes) compared intravitreal dexamethasone implant 0.7mg with intravitreal antiVEGF (bevacizumab and ranibizumab). There was moderate‐certainty evidence that visual acuity improved slightly less with dexamethasone compared with antiVEGF at 12 months (MD 0.07 logMAR, 95% CI 0.04 to 0.09 logMAR; 2 trials; 451 participants/eyes; I(2) = 0%). The RR of gain of three or more lines of visual acuity was inconsistent between trials, with one trial finding no evidence of a difference between dexamethasone and bevacizumab at 12 months (RR 0.99, 95% CI 0.70 to 1.40; 1 trial; 88 eyes), and the other, larger trial finding the chances of vision gain were half with dexamethasone compared with ranibizumab (RR 0.50, 95% CI 0.32 to 0.79; 1 trial; 432 participants). The certainty of evidence was low. Cataract progression and the need for IOP‐lowering medications increased more than 4 times with dexamethasone implant compared to antiVEGF (moderate‐certainty evidence). One trial (560 eyes) compared intravitreal fluocinolone implant 0.19mg with sham. There was moderate‐certainty evidence that visual acuity improved slightly more with fluocinolone at 12 months (MD −0.04 logMAR, 95% CI −0.06 to −0.01 logMAR). There was moderate‐certainty evidence that an improvement in visual acuity of three or more lines was more common with fluocinolone than with sham at 12 months (RR 1.79, 95% CI 1.16 to 2.78). Fluocinolone also increased the risk of cataract progression (RR 1.63, 95% CI 1.35 to 1.97; participants = 335; moderate‐certainty evidence), which occurred in about 8 in 10 participants, and the use of IOP‐lowering medications (RR 2.72, 95% CI 1.87 to 3.98; participants = 558; moderate‐certainty evidence), which were needed in 2 to 3 out of 10 participants. One small trial with 43 participants (69 eyes) compared intravitreal triamcinolone acetonide injection 4 mg with sham. There may be a benefit in visual acuity at 24 months (MD −0.11 logMAR, 95% CI −0.20 to −0.03 logMAR), but the certainty of evidence is low. Differences in adverse effects were poorly reported in this trial. Two trials (615 eyes) compared intravitreal triamcinolone acetonide injection 4mg with laser photocoagulation and reached discordant results. The smaller trial (31 eyes followed up to 9 months) found more visual acuity improvement with triamcinolone (MD −0.18 logMAR, 95% CI −0.29 to −0.07 logMAR), but a larger, multicenter trial (584 eyes, 12‐month follow‐up) found no evidence of a difference regarding change in visual acuity (MD 0.02 logMAR, 95% CI ‐0.03 to 0.07 logMAR) or gain of three or more lines of visual acuity (RR 0.85, 95% CI 0.55 to 1.30) (overall low‐certainty evidence). Cataract progression was about three times more likely (RR 2.68, 95% CI 2.21 to 3.24; moderate‐certainty evidence) and the use of IOP‐lowering medications was about four times more likely (RR 3.92, 95% CI 2.59 to 5.96; participants = 627; studies = 2; I(2) = 0%; moderate‐certainty evidence) with triamcinolone. About 1 in 3 participants needed IOP‐lowering medication. One small trial (30 eyes) compared intravitreal triamcinolone acetonide injection 4mg with intravitreal antiVEGF (bevacizumab or ranibizumab). Visual acuity may be worse with triamcinolone at 12 months (MD 0.18 logMAR, 95% CI 0.10 to 0.26 logMAR); the certainty of evidence is low. Adverse effects were poorly reported in this trial. Four trials reported data on pseudophakic participants, for whom cataract is not a concern. These trials found no decrease in visual acuity in the second treatment year due to cataract progression. AUTHORS' CONCLUSIONS: Intravitreal steroids may improve vision in people with DME compared to sham or control. Effects were small, about one line of vision or less in most comparisons. More evidence is available for dexamethasone or fluocinolone implants when compared to sham, and the evidence is limited and inconsistent for the comparison of dexamethasone with antiVEGF treatment. Any benefits should be weighed against IOP elevation, the use of IOP‐lowering medication and, in phakic patients, the progression of cataract. The need for glaucoma surgery is also increased, but remains rare