Sunday, 22 February 2015
Diabetes is a significant risk factor for developing eye diseases. The most common diabetic eye disease and a leading cause of blindness is diabetic retinopathy, which is caused by elevated blood sugar levels damaging the blood vessels of the retina and affects approximately 7.7 million Americans. About 750,000 Americans with diabetic retinopathy have diabetic macular edema (DME) in which fluid leaks into the macula, the area of the retina used when looking straight ahead. The fluid causes the macula to swell, blurring vision. "DME is the leading cause of moderate vision loss in working-age adults with diabetes. With the rate of diabetes increasing dramatically worldwide, many individuals will be at risk for vision loss from diabetic eye complications and DME is a major global health concern," says Jennifer K. Sun, M.D., M.P.H., a member of the study research team and writing committee, and an Investigator in the Section on Vascular Biology, an ophthalmologist in Beetham Eye Institute at Joslin and an Assistant Professor at Harvard Medical School.
In an earlier study, Joslin researchers reported that VEGF, a major growth factor for blood vessels, is elevated in the eye fluids of patients with proliferative diabetic retinopathy and DME, causing leakage and the growth of abnormal blood vessels. Over the past few years, drugs that target VEGF have become a standard treatment for DME, providing a preferred alternative or adjunct to laser treatment. The standard Medicare per-injection costs of the three anti-VEGF drugs evaluated in the study are about $1960 for aflibercept (Eylea), $1200 for ranibizumab (Lucentis) and $70 for bevacizumab (Avastin).
At the start of the trial, 660 adults with DME were enrolled: their average age was 61 years and 90 percent had type 2 diabetes. About half of the participants had 20/32 or 20/40 vision and the other half had vision of 20/50 or worse. They were randomized into three treatment groups and received the assigned study drug by injection into the eye until the DME resolved or stabilized. Participants on bevacizumab and ranibizumab received, on average, 10 injections, versus nine for those on aflibercept.
One year after starting treatment, all participants had improved vision. Those with mild vision loss (20/32 to 20/40) at baseline in all three treatment groups gained on average almost two lines on an eye chart. For participants with more severe vision loss (20/50 or worse), aflibercept improved vision on average nearly four lines, bevacizumab about 2.5 lines, and ranibizumab almost three lines.
"The results clearly remove any doubts about anti-VEGF drugs’ efficacy in treating DME. All three drugs improved vision substantially, with aflibercept showing more visual gains in patients with worse vision at the start of the trial. Physicians now have robust data to help them counsel patients and make informed decisions regarding treatment options," says study co-author Lloyd P. Aiello, M.D., Ph.D., Professor of Ophthalmology at Harvard Medical School, Director of Joslin’s Beetham Eye Institute, co-head of Joslin's Section of Vascular Cell Biology, and founding chair of the DRCR Network.
In light of these positive results, "it is more important than ever for patients with diabetes to be evaluated on a regular basis for eye disease and receive treatment promptly once indicated as we now have excellent success in treating patients with DME," says Dr. Aiello.
The trial was supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services. Regeneron Pharmaceutical provided the aflibercept and Genentech provided the ranibizumab for the study. The DRCR.net had complete control over the design of the study, data ownership and content of presentations and publications related to this study.
Source: Joslin Diabetes Center
Tuesday, 16 September 2014
A new study published in the September issue of The FASEB Journal identifies a novel strategy to diagnose diabetic retinopathy before irreversible structural damage has occurred. This advance involves quantifying the early molecular changes caused by diabetes on the endothelium of retinal vessels. Using new probes developed by scientists, they were able to distinguish the early molecular development of diabetic retinopathy.
"My goal is to establish a versatile clinical tool that alerts of a disease process right when the first molecular changes take place. This will then provide ample opportunity to act, as opposed to merely acknowledge that there is structural damage that we cannot do anything about," said Ali Hafezi-Moghadam, M.D., Ph.D., a researcher involved in the work from the Center for Excellence in Functional and Molecular Imaging at Brigham and Women's Hospital and Harvard Medical School in Boston, MA. "Here, we have shown it in an important disease, the diabetic retinopathy, but there is no reason to stop there."
Hafezi-Moghadam and colleagues identified a target on the intraluminal surface of the retinal vessels that is expressed at higher levels in diabetes. They found significantly more vascular endothelial growth factor receptor 2 (VEGFR-2) in the diabetic micro-vessels compared to control. They then custom-generated molecular probes and characterized their binding properties. Light-based live imaging was then used to quantify binding interaction. An unexpected finding in this work was that not only was VEGFR-2 higher in the retinas of diabetic animals as well as humans, but the molecule was found in the retinal micro vessels, not in the larger vessels. When the imaging probes were injected into the blood stream of living normal and diabetic animals, they circulated throughout the animal's vasculature. With the help of live imaging of the retinal vessels, it was possible to visualize the interaction of individual probes with their endothelial targets. The probes transiently interacted with the intraluminal surfaces. In comparison, control probes with a surface moiety that does not interact with the inner vascular lumen freely flowed through the retinal micro vessels. Since the probe interaction with the inner vessel wall can be deduced to individual molecular interactions, the information gained from this study provides quantitative knowledge of target molecules in the retinal micro vessels.
"This study should be a huge eye-opener for doctors hoping to prevent eye disease resulting from diabetes," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "This study shows that it is possible to do this, and the next step is to make this accessible at the clinical level. The sooner doctors can detect that their patients might have a vision problem, the more time they have to save someone's sight."
Source: Federation of American Societies for Experimental Biology via EurekAlert
Monday, 15 September 2014
KalVista is an ophthalmology company with a primary focus on diabetic macular edema and the discovery and development of serine protease inhibitors. According to a press release on their website, the study is an open label, single ascending dose study to investigate the safety, tolerability and pharmacodynamics of KVD001 delivered by intravitreal injection (ClinicalTrials.gov identifier NCT02193113). First patients were dosed in August and recruitment is ongoing at five centers in the US.
Although VEGF inhibitors such as Lucentis can benefit DME, a significant number of patients do not respond fully to these agents and have limited treatment options. Plasma kallikrein inhibitors target a distinct molecular pathway and, according to KalVista, have the potential to offer those patients an effective treatment option.
Dr Jennifer Sun said: "DME is a leading cause of adult visual loss in developed countries and new approaches for DME are a major unmet medical need. KalVista’s novel plasma kallikrein inhibitor could offer a therapeutic approach to the treatment of the condition that targets different molecular pathways than currently available therapies. We look forward to completing the first clinical study with KVD001."
Andrew Crockett, KalVista CEO, said: "Today’s announcement of the start of clinical development for KVD001 is a significant step for KalVista. Our collaboration with the JDRF has been very productive and we are delighted to begin this study of a new treatment we hope will ultimately improve outcomes for patients with what is a very serious complication in diabetes."
Plasma kallikrein is a serine protease that represents an attractive drug target in people with diabetic retinopathy as it is has been shown to contribute to blood vessel leakage and thickening of the retina through the collaborative work of Drs. Edward P Feener and Lloyd Paul Aiello at the Joslin Diabetes Center. The detrimental effects of plasma kallikrein on the retina in patients with diabetes are mediated by mechanisms that are independent of vascular endothelial growth factor (VEGF), which has been an area of intense recent interest as a target for treating DME. However, while intravitreal VEGF inhibitors have shown clear benefit in clinical trials in many patients through reducing macular edema and increasing visual acuity, a substantial proportion of DME patients do not respond fully to anti-VEGF treatment. KalVista’s approach, targeting plasma kallikrein inhibition, has the potential to add to the treatment options for sufferers of DME including those that are non-responsive to VEGF inhibitors.
Source: KalVista Pharmaceuticals
Thursday, 31 July 2014
"I wasn't sure what gastric bypass would do to diabetic retinopathy," lead author Rishi P. Singh, MD, staff physician at the Cole Eye Institute, in Cleveland Clinic, Ohio, told Medscape Medical News. "I was pleasantly reassured by the fact that they didn't have a higher incidence of retinopathy or significant progression of the disease."
Dr. Singh reported 2-year ophthalmology findings from STAMPEDE at the recent American Diabetes Association (ADA) 2014 Scientific Sessions. "This is the first time that a prospective, randomized clinical trial has shown that intensive medical management vs gastric bypass doesn't appear to increase the retinopathy incidence or progression, nor does it increase the rate of vision loss or changes in intraocular blood pressure (a sign of glaucoma)," he commented.
"The take-away point is that... ophthalmic management of our [diabetic] patients through yearly evaluations — which is what the ADA and [American Academy of Ophthalmology] AAO recommend — should still continue," he cautioned."Despite the fact that these patients had essentially normal HbA1c values [at] year 2 in the gastric-bypass group, that doesn't mean that they were free of retinopathy, so it's important to follow those patients long term and monitor them for eye complications."
Asked to comment, bariatric surgeon Bruce M. Wolfe, MD, at Oregon Health and Science University, Portland, said it will take many more years to begin to see any impact upon retinopathy. "The induction of remission or improvement in diabetes control is positive for the patient, but drawing conclusions about the many-year process of diabetic complications of diabetic neuropathy or diabetic retinopathy is premature."
Patients who are informed that their diabetes has gone into remission after they have had bariatric surgery may think, "I don't need to go to these eye assessments any more," he added, but that would be too hasty, he stressed.
Diabetes is likely to recur in some patients — possibly in 5, 10, or 20 years — and those patients are at increased risk for microvascular complications. "I agree with the authors that it is important for diabetic patients to continue to have regular eye examinations," which can spot any changes and lead to earlier treatment to delay disease progression, he told Medscape Medical News.
After patients with type 2 diabetes have bariatric surgery, their glycemic control improves. However, it is not yet known how these rapid changes in HbA1c affect the progression of microvascular complications such as retinopathy. There have been some reports of improvements, but other studies have reported worsening of these outcomes, as was seen in the DCCT trial or in a small series of patients presented at last year's ADA meeting, Dr. Singh explained.
STAMPEDE randomized 150 obese patients with uncontrolled type 2 diabetes to intensive medical therapy alone (50 patients), Roux-en-Y gastric-bypass surgery (50) or sleeve gastrectomy (50). To be eligible, patients had to be 20 to 60 years old and have an HbA1c greater than 7% and a body mass index (BMI) of 27 to 43 kg/m2.
Intensive medical therapy consisted of antidiabetic therapeutic agents plus diet and lifestyle counseling and regular follow-up, with a target HbA1c of 6% or lower. Patients had had diabetes for about 8.5 years, and more than half were taking 3 or more antidiabetic medications.
The 3-year nonophthalmic primary and secondary outcomes were recently presented at the American College of Cardiology meeting and simultaneously published. Mean HbA1c dropped by 1.1% from 9.0% at baseline in those who got medical therapy, by 2.8% from 9.3% in the gastric-bypass group, and by 2.7% from 9.5% in the sleeve-gastrectomy patients. The trial was also designed to measure ophthalmic outcomes at baseline and at 2 years and 5 years, as secondary outcomes.
About 80% of the patients had no evidence of retinopathy at baseline. From baseline to 2 years, there was no significant change in retinopathy scores for patients who had no retinopathy or mild to severe nonproliferative retinopathy or proliferative retinopathy, for patients who had received each of the 3 treatments. The mean baseline and 2-year visual acuity scores were logMAR 0 (20/20) for each of the 3 treatment groups.
Dr. Singh said that in all honesty, longer-term follow-up will be needed to properly gauge the effect of bariatric surgery on diabetic retinopathy. Progressing from mild to severe diabetic retinopathy is "typically a process that would potentially occur anywhere from 10 to 15 years [out], but it can be shorter depending on how bad sugar control really is," he explained. "If HbA1c is, for example, 11%, 12%, or 13%, those patients can progress twice as fast as those with HbA1c of 6% or 7%. It [also] depends on the length of time a patient has diabetes."
The 5-year data from STAMPEDE should shed more light on this microvascular outcome, he concluded.
Dr. Singh receives consulting fees from Alcon Laboratories, Genentech, Regeneron, ThromboGenics, and Valeant Pharmaceuticals and is on the speakers' bureau for Genentech, Regeneron, and ThromboGenics.
Source: American Diabetes Association 2014 Scientific Sessions via Marlene Busko, Medscape Medical News
Tuesday, 1 July 2014
Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor, and leukotriene B4 receptor 1 levels, leukotriene B4 generation and superoxide production may be potential pathogenic markers for diabetic retinopathy in young patients with type 1 diabetes, according to study data presented.
“If we could use this already U.S. Food and Drug Administration-approved drug to block our leukotriene pathway, it would be a great way to intervene and actually help prevent diabetic retinopathy,” Marcella Luercio, MD, of Case Western University, said during a presentation at the American Diabetes Association’s 74th Scientific Sessions. “Our preliminary studies here show that when we treat leukocytes isolated from diabetic patients with montelukast sodium, we can inhibit LTB4 production in almost all of these patients. It actually goes down significantly. If we can block this, we would hope that we could prevent some diabetic retinopathy in our young diabetes patients.”
The study presented included 28 patients with type 1 diabetes (mean HbA1c > 6.5%; diabetes duration of at least 5 years) and 16 age-matched healthy controls.
Luercio and colleagues assessed leukotriene B4 receptor 1 (BLT1) levels, leukotriene B4 generation (LTB4), and superoxide production and effects on endothelial cells.
Data indicated that patients with diabetes demonstrated a 1.4-fold increase in BLT1 levels (P = .002), with levels increasing among patients with worsened glycemia and longer diabetes duration, compared with patients without diabetes.
Leukocyte levels in patients with a diabetes duration of more than 10 years also appeared to generate a 1.3-fold increase in LTB4 (P = .007), and produced a twofold increase of superoxide (P = .028), according to the researchers.
“Perhaps these markers could be used... to identify young patients we see each day in the clinic who could be at high risk for diabetic retinopathy to be treated with montelukast or other therapeutic agents that are yet to be discovered,” Luercio said.
Source: Samantha Costa, Healio
Monday, 30 June 2014
“These data are clinically relevant for ophthalmologists and endocrinologists for the treatment of diabetic retinopathy because the RETeval machine (LKC Technologies) is a new tool for screening patients with diabetes for eye disease that can be performed by the primary care physician,” April Y. Maa, MD, of the Atlanta VAMC/Emory Eye Center, told Ocular Surgery News. “It does not use photographs (ie, the device is not a camera), which traditionally have a failure rate of 10% to 15%, and instead measures and uses electrical signals generated by the eye (30Hz ERG), to determine level of retinopathy.”
LKC Technologies Inc states that this revolutionary device measures the 30 Hz flicker implicit time and amplitude, which has a strong correlation to retinal ischemic diseases such as diabetic retinopathy, and can be used to distinguish between ischemic and non-ischemic CRVO.
Preliminary data indicated that the RETeval machine was easy to use, with no patient dilation or skin preparation required, and was user-friendly, requiring minimal training.
The most surprising finding, Maa said, was how quickly the test could be performed.
“According to our poster graph, it took only 2.3 minutes on average to perform the test in both eyes of a patient,” Maa said.
In their study, Maa and colleagues classified 500 patients with diabetes into one of five groups: those with no diabetic retinopathy with ETDRS level 10, those with mild diabetic retinopathy and ETDRS levels 14 to 35, those with moderate diabetic retinopathy without clinically significant macular edema (CSME) and ETDRS levels 43 to 47, those with mild-to-moderate diabetic retinopathy with CSME and ETDRS levels 10 to 47, those with severe diabetic retinopathy or proliferative diabetic retinopathy with ETDRS levels 53 and higher. Of the initial 500 patients, 392 completed the study.
After completion of the RETeval test, patients were dilated and ETDRS-compliant seven-field stereo fundus photographs were taken. The photographs were reviewed in a double-masked fashion in a reading center, according to data.
The RETeval device had a technical failure rate of 0.5% (n = 2) compared with a significantly higher failure rate of 15% (n = 57) using fundus photography (P < .001), according to Maa. “Our preliminary data suggest the RETeval device is accurate in discerning levels of diabetic retinopathy, but we need further data analysis to confirm these data,” Maa said. "The device is not U.S. Food and Drug Administration-approved yet, and we are in the process of completing our data analysis.”
Source: LKC Technologies via Samantha Costa, Healio
Thursday, 24 April 2014
Currently, there is debate about the role of transforming growth factor-beta (TGF-β1) in the development of DR. This study searched multiple databases to identify publications that evaluated correlations between polymorphisms in the TGF-β1 gene and susceptibility to DR.
The authors found that one specific polymorphism was associated with decreased susceptibility to DR: +869T/C (L10P). This was true in both the allele model and the recessive model.
Strengths of this study include the detailed search of databases as well as the strict selection and exclusion criteria. However, a limitation in this study is a small number of publications included for analysis. Nonetheless, this is the first study to link the +869T/C (L10P) polymorphism to decreased susceptibility to DR, suggesting its important future role in DR prevention.
Source: PLoS One
Wednesday, 23 April 2014
"We had not expected to see such striking changes to the retinas at such early stages," said Ann Elsner, professor and associate dean in the IU School of Optometry and lead author of the study. "We set out to study the early signs, in volunteer research subjects whose eyes were not thought to have very advanced disease. There was damage spread widely across the retina, including changes to blood vessels that were not thought to occur until the more advanced disease states."
These important early-warning signs were invisible to existing diagnostic techniques, requiring new technology based on adaptive optics, and known as a confocal adaptive optics scanning laser ophthalmoscope (AOSLO). Stephen Burns, professor and associate dean at the IU School of Optometry, designed and built an instrument that used small mirrors with tiny moveable segments to reflect light into the eye to overcome the optical imperfections of each person's eye.
"It is shocking to see that there can be large areas of retina with insufficient blood circulation," he said. "The consequence for individual patients is that some have far more advanced damage to their retinas than others with the same duration of diabetes."
Because these changes had not been observable in prior studies, it is not known whether improved control of blood sugar or a change in medications might stop or even reverse the damage. Further research can help determine who has the most severe damage and whether the changes can be reversed.
The study, "In vivo adaptive optics microvascular imaging in diabetic patients without clinically severe diabetic retinopathy," was published in the journal Biomedical Optics Express.
Diabetes has long been known to damage the retina, the irreplaceable network of nerve cells that capture light and give the first signal in the process of seeing. This damage to the retina, known as diabetic retinopathy, is the leading cause of vision loss in the U.S. for individuals under the age of 75.
Diabetes also is known to result in a variety of types of damage to capillaries, the body's smallest blood vessels. The more commonly known changes, such as microaneurysms along the capillaries, were also present in the study, but seen in much greater detail. In addition to the corkscrew appearance and microaneurysms, along with the hemorrhages in the later stages of the disease, there is also a thickening of the walls of blood vessels. This is thought to be associated with poor blood flow or failure to properly regulate blood flow.
In the study, patients with diabetes had significantly thicker blood vessel walls than found in controls of similar ages, even for relatively small diameter blood vessels. The capillaries varied in width in the diabetic patients, with some capillaries closed so that they no longer transported blood within the retina. On average, though, the capillaries that still had flowing blood were broader for the patients with diabetes. These diabetic patients had been thought to have fairly mild symptoms. In fact, the transport of oxygen and glucose to the retina is already compromised.
Previous diagnostic techniques have been unable to uncover several of these changes in living patients. Simply magnifying the image of the retina is not sufficient. The view through the imperfect optics of the human eye has to be corrected.
The instrument designed by Burns takes advantage of adaptive optics to obtain a sharp image, and also minimized optical errors throughout the instrument. Using this approach, the tiny capillaries in the eye appear quite large on a computer screen. These blood vessels are shown in a video format, allowing careful focus and observation of blood cells moving through the blood vessels. After imaging each patient's eye, highly magnified retinal images are then pieced together with software, providing still images or videos.
Research reported in this press release was supported by the National Eye Institute of the National Institutes of Health under award number R01EY007624 and R01EY004395 and Indiana University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Co-authors include Toco Y. Chui, Dean A. VanNasdale Jr., Christopher A. Clark, Thomas J. Gast and Victor E. Malinovsky, IU School of Optometry; and Anh-Danh T. Phan, Eugene and Marilyn Glick Eye Institute, IU School of Medicine.
Source: Indiana University, Bloomington and Biomedical Optics Express
Friday, 7 March 2014
Bayer HealthCare and Regeneron Announce Regulatory Submission of EYLEA® (aflibercept) Injection for the Treatment of Diabetic Macular Edema in Japan
TARRYTOWN, N.Y., March 3, 2014 /PRNewswire/ -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that Bayer HealthCare's Japanese subsidiary, Bayer Yakuhin, Ltd., has submitted an application for marketing authorization for EYLEA® (aflibercept) Injection for the treatment of patients with diabetic macular edema (DME) to the Japanese Ministry of Health, Labour and Welfare (MHLW).
"Clinically significant DME is a leading cause of vision loss in the working-age population suffering from diabetes. With increasing rates of diabetes worldwide, there continues to be a need for new treatment options," said George D. Yancopoulos, M.D., Ph. D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "We are pleased with this regulatory submission and hope that if approved, EYLEA will provide a new option for the treatment of DME in Japan."
The submission of EYLEA for DME in Japan is based on data from the VISTA-DME, VIVID-DME and VIVID-Japan studies. In the Phase 3 VIVID-DME and VISTA-DME trials, EYLEA 2 milligrams (mg) dosed monthly and EYLEA 2 mg dosed every two months (after 5 initial monthly injections) achieved the primary endpoint of significantly greater improvement in best-corrected visual acuity (BCVA) from baseline compared to laser photocoagulation at 52 weeks. In these trials, EYLEA was generally well tolerated with a similar overall incidence of adverse events (AEs), ocular serious AEs, and non-ocular serious AEs across the treatment groups and the laser control group. Arterial thromboembolic events as defined by the Anti-Platelet Trialists' Collaboration (non-fatal stroke, non-fatal myocardial infarction, and vascular death) also occurred at similar rates across the treatment groups and the laser control group. The most frequent ocular treatment emergent AEs (TEAEs) observed in the VIVID-DME and VISTA-DME trials included conjunctival hemorrhage, eye pain, and vitreous floaters. The most frequent non-ocular TEAEs included hypertension and nasopharyngitis, which occurred with similar frequency in the treatment groups and the laser control group.
One-year data from the VIVID-DME and VISTA-DME trials have been presented at medical congresses in the U.S. and Europe. Full two-year data from the VISTA-DME trial will be presented at upcoming medical conferences. Two-year data from the similarly designed VIVID-DME trial are expected later in 2014. Each of the VISTA-DME and the VIVID-DME trials is expected to continue as planned up to 148 weeks.
EYLEA was approved in the United States for the treatment of neovascular (wet) Age-related Macular Degeneration (AMD) in November 2011 and for Macular Edema following Central Retinal Vein Occlusion (CRVO) in September 2012. EYLEA has also been approved in the European Union (EU) and other countries for use in wet AMD and Macular Edema following CRVO. Regulatory submissions have also been made in the U.S. and the EU for EYLEA for the treatment of DME. A regulatory submission has been made in the U.S. for EYLEA for the treatment of macular edema following Branch Retinal Vein Occlusion (BRVO).
Bayer HealthCare and Regeneron are collaborating on the global development of EYLEA. Regeneron maintains exclusive rights to EYLEA in the United States. Bayer HealthCare licensed the exclusive marketing rights outside the United States, where the companies share equally the profits from sales of EYLEA, except for Japan where Regeneron receives a percentage of net sales.
Source: Regeneron Pharmaceuticals
Thursday, 6 March 2014
Two-Year Results From Phase 3 VISTA Trial of EYLEA® (aflibercept) Injection for the Treatment of Diabetic Macular Edema Show Sustained Improvement in Vision
TARRYTOWN, N.Y., Feb. 10, 2014 /PRNewswire/ -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Bayer HealthCare today announced that in the Phase 3 VISTA-DME trial of EYLEA® (aflibercept) Injection for the treatment of diabetic macular edema (DME), EYLEA 2 milligrams (mg) dosed monthly (2Q4) and EYLEA 2 mg dosed every two months (after 5 initial monthly injections, 2Q8) showed a sustained improvement from baseline in best corrected visual acuity (BCVA) at week 100, compared to laser photocoagulation. The 52-week results (primary analyses) from this study have been previously reported.
Patients in the VISTA-DME trial were randomized to receive either EYLEA 2Q4 (n=155), EYLEA 2Q8 (n=152), or the comparator treatment of laser photocoagulation (n=154).
After two years, patients receiving EYLEA 2Q4 had a mean change from baseline in BCVA of 11.5 letters (12.5 letters at 52 weeks). Patients receiving EYLEA 2Q8 had a mean change from baseline in BCVA of 11.1 letters (10.7 letters at 52 weeks). Patients in the laser photocoagulation treatment group had a mean change from baseline in BCVA of 0.9 letters (0.2 letters at 52 weeks).
"These data showed that treatment with EYLEA in this trial improved vision and maintained the improvement over two years in patients with diabetic macular edema," said George D. Yancopoulos, M.D., Ph. D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "These results are particularly encouraging given that 43 percent of patients in this study had previously received anti-VEGF therapy."
In this trial, EYLEA was generally well tolerated with a similar overall incidence of adverse events (AEs), ocular serious AEs, and non-ocular serious AEs across the EYLEA treatment groups and the laser control group. AEs were typical of those seen in other studies in patients with diabetes receiving intravitreal anti-VEGF therapy. The most frequent ocular AEs observed in the VISTA-DME trial included conjunctival hemorrhage, eye pain, and vitreous floaters. The most frequent non-ocular AEs included hypertension, anemia, and urinary tract infection. Arterial thromboembolic events as defined by the Anti-Platelet Trialists' Collaboration (non-fatal stroke, non-fatal myocardial infarction, and vascular death) were similar across the treatment groups and the laser control group with events occurring in 13 out of 155 patients in the EYLEA 2Q4 group, 11 out of 152 patients in the EYLEA 2Q8 group, and 9 out of 154 patients in the laser group. Eight out of 155 patients died in the EYLEA 2Q4 group, 4 out of 152 patients in the EYLEA 2Q8 group, and 3 out of 154 patients in the laser treatment group.
Full two-year data from the VISTA-DME trial will be presented at upcoming medical conferences. Two-year data from the similarly designed VIVID-DME trial are expected later in 2014. Both the VISTA-DME and the VIVID-DME trials will continue as planned up to 148 weeks.
EYLEA was approved in the United States for the treatment of neovascular (wet) Age-related Macular Degeneration (AMD) in November 2011 and for Macular Edema following Central Retinal Vein Occlusion (CRVO) in September 2012. EYLEA has also been approved in the European Union (EU), Japan, and other countries for use in wet AMD and Macular Edema following CRVO. Regulatory submissions have also been made in the U.S. and the EU for EYLEA for the treatment of Diabetic Macular Edema, and in Japan for the treatment of choroidal neovascularization secondary to pathologic myopia (mCNV).
Bayer HealthCare and Regeneron are collaborating on the global development of EYLEA. Regeneron maintains exclusive rights to EYLEA in the United States. Bayer HealthCare licensed the exclusive marketing rights outside the United States, where the companies share equally the profits from sales of EYLEA, except for Japan where Regeneron receives a percentage on net sales.
About the EYLEA® (aflibercept) Injection Phase 3 DME Program
The global Phase 3 DME program consists of three double-masked trials: VIVID-DME, VISTA-DME, and VIVID-EAST-DME, and one open-label, single-arm safety trial in Japanese patients (VIVID-Japan). All three double-masked studies have three treatment arms, where patients are randomized to receive either EYLEA 2 mg monthly, EYLEA 2 mg every two months (after 5 initial monthly injections), or the comparator treatment of laser photocoagulation. Based on protocol specified criteria, patients were eligible to receive rescue treatment from week 24 onwards. Rescue treatment in the EYLEA groups was adjunct laser treatment, and in the laser control group it was EYLEA 2 mg. The primary endpoint of all three studies is the mean change in best-corrected visual acuity from baseline, as measured on the Early Treatment Diabetic Retinopathy Scale (ETDRS) eye chart, a standard chart used in research to measure visual acuity. The VIVID-DME, VISTA-DME, and VIVID-EAST-DME studies are ongoing.
About EYLEA® (aflibercept) Injection for Intravitreal Injection
Vascular Endothelial Growth Factor (VEGF) is a naturally occurring protein in the body. In patients with diabetic macular edema (DME), hyperglycemia-induced vascular dysfunction and hypoxia result in elevated intraocular VEGF levels in the eye and resultant blood vessel permeability that leads to macular edema, which can result in vision loss.
EYLEA, known in the scientific literature as VEGF Trap-Eye, is a recombinant fusion protein, consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and formulated as an iso-osmotic solution for intravitreal administration. EYLEA acts as a soluble decoy receptor that binds VEGF-A and placental growth factor (PlGF) and thereby can inhibit the binding and activation of their cognate VEGF receptors.
Source: Regeneron Pharmaceuticals
Friday, 21 February 2014
OHR Pharmaceutical Inc, a pharmaceutical company focused on the development of novel therapeutics for large unmet medical needs, announced that a case report on the first patient treated in an ongoing investigator sponsored trial ("IST") with Squalamine eye drops in proliferative diabetic retinopathy was presented on Wednesday at the 37th Annual Macula Society Meeting, in Key Largo, Florida. In PDR, abnormal blood vessels (neovascularization) grow from the retina into the vitreous cavity of the eye, resulting in blindness if untreated. The case report was presented by the lead investigator, Michael J. Elman, M.D., Director of the Elman Retina Group from Baltimore, Maryland.
Dr. Elman's oral presentation discussed the case of a treatment naïve patient diagnosed with PDR. The data demonstrated that topical application of squalamine eye drops in a monotherapy regimen, BID and then QID, was associated with regression of retinal neovascularization within two months. The retinal neovascularization remained regressed throughout the six months of QID Squalamine drop therapy. One month after cessation of Squalamine treatment, the abnormal blood vessels returned in this patient's retina, and continued to grow through month 2, the furthest time point measured.
"These are promising results which provide the first evidence in a human eye that topical application of Squalamine can produce a biological effect in retinal disease," said Dr. Michael J. Elman, Principal Investigator for the OHR-003 clinical trial. "This regression of these vision threatening blood vessels while on topical Squalamine treatment, coupled with the return and worsening of the neovascularization once Squalamine was stopped, supports a therapeutic treatment response of the neovascularization to topical Squalamine drops when used as monotherapy."
Irach Taraporewala, Chief Executive Officer of Ohr Pharmaceutical, also commented, "We are encouraged by the early data observed in Dr. Elman's case report from a single patient and look forward to seeing further results once the trial is complete. There is a clear unmet medical need for topical therapies to treat back-of-the-eye diseases. We look forward to the interim data from the ongoing Phase 2 wet-AMD clinical trial in the second quarter of 2014. The company continues to expand the Squalamine eye drop clinical programs and we expect to have two additional investigator sponsored trials initiated in diabetic macular edema during the current quarter."
This ongoing 5 patient OHR-003 trial is designed to determine the efficacy of topical Squalamine Lactate Ophthalmic Solution, 0.2%, in the treatment of retinal neovascularization resulting from proliferative diabetic retinopathy. The endpoints include regression of neovascularization, anatomical measurements, visual acuity, and safety parameters.
Squalamine is an anti-angiogenic small molecule with a novel intracellular mechanism of action, which counteracts multiple growth factors implicated in the angiogenesis process. OHR Pharmaceutical has developed a novel eye drop formulation of Squalamine for the treatment of wet-AMD, designed for self-administration, which may provide several potential advantages over the FDA approved current standards of care, which require intravitreal injections directly into the eye. The drug, using an intravenous administration in over 250 patients in Phase I and Phase II trials for the treatment of wet-AMD, showed favorable biological effect and maintained and improved visual acuity outcomes. In May 2012, the Squalamine Eye Drop program was granted Fast Track Designation by the U.S. FDA. A Phase II randomized, double blind, placebo controlled study (OHR-002) to evaluate the efficacy and safety of Squalamine Eye Drops for the treatment of wet-AMD is currently enrolling patients at more than twenty clinical sites in the U.S. Two additional investigator sponsored trials (IST) are evaluating squalamine eye drops for the treatment of proliferative diabetic retinopathy and retinal vein occlusion, with two additional IST's expected to be initiated in diabetic macular edema in the first quarter of 2014.
Source: OHR Pharmaceutical Inc
Thursday, 20 February 2014
Diabetic retinopathy affects more than a quarter of adults with diabetes and threatens the vision of more than 600,000 people in the United States. Doctors had previously thought most of the impairment of vision in diabetic retinopathy came from damage to the blood vessels induced by high blood sugar, but had known that dopamine, a vital neurotransmitter in the brain, was also important in the retina.
"There was some evidence already that dopamine levels were reduced in diabetic retinopathy, but what’s new here is: we can restore dopamine levels and improve visual function in an animal model of diabetes," says Machelle Pardue, PhD, associate professor of ophthalmology at Emory University School of Medicine and research career scientist at the Atlanta VA Medical Center.
The first author of the paper is MD/PhD student Moe Aung. Senior authors are Pardue and P. Michael Iuvone, PhD, professor of ophthalmology and pharmacology and director of vision research at Emory Eye Center.
Aung and his colleagues examined mice that were made diabetic by treating them with streptozocin, which is toxic to insulin-producing cells in the pancreas. By injecting the mice with L-DOPA after they received streptozocin, the researchers could delay the appearance of visual problems by weeks and lessen the severity of the visual defects. Researchers also found that the visual benefits of L-DOPA originated from the retinas, since treatment improved retinal responses, as measured by electroretinography, to levels similar to control animals.
L-DOPA, a precursor to dopamine, is part of the most common drug treatment for Parkinson's disease. The symptoms of Parkinson's (tremors and movement difficulties, as well as disturbances in sleep, digestion and cognition) are caused by the death of dopamine-producing cells in the brain. L-DOPA is usually combined with carbidopa to combat side effects and increase uptake in the brain.
The researchers also measured the effects of other dopamine-related treatments on visual function. Dopamine receptor agonists – drugs that mimic the action of dopamine – are sometimes prescribed for Parkinson's patients who do not respond to L-DOPA. Neurons and retinal cells have several molecules that enable them to respond to dopamine, and individual drugs affect them to varying degrees. Working with Iuvone, MSP graduate student Chad Jackson, now at Vanderbilt, found that giving diabetic mice dopamine receptor agonists that acted on the receptor D1R improved the ability to see fine lines (acuity), while drugs that act on D4R improve contrast sensitivity.
"This is important because it shows that treatments targeting dopamine could be beneficial to patients with established diabetes," says Iuvone. "It should be straightforward to try L-DOPA or dopamine receptor agonist treatment in adults, although L-DOPA could have complications in children. Bromocriptine, a dopamine receptor agonist, is already FDA-approved to treat type 2 diabetes. It will be important to determine if the same dopamine receptors modulate acuity and contrast sensitivity in humans."
The research was supported by the National Eye Institute (P30 EY006360 and R01 EY004864), the National Institute of Diabetes and Digestive and Kidney Diseases (DK07601-01), the Department of Veterans Affairs, Research to Prevent Blindness, the Juvenile Diabetes Research Foundation and Children's Healthcare of Atlanta.
Source: Emory University School of Medicine
Friday, 3 January 2014
Although other research groups and companies have created hand-held devices using similar technology, the new design is the first to combine cutting-edge technologies such as ultrahigh-speed 3-D imaging, a tiny micro-electro-mechanical systems (MEMS) mirror for scanning, and a technique to correct for unintentional movement by the patient. These innovations, the authors say, should allow clinicians to collect comprehensive data with just one measurement.
Normally, to diagnose retinal diseases, an ophthalmologist or optometrist must examine the patient in his or her office, typically with table-top instruments. However, few people visit these specialists regularly. To improve public access to eye care, the MIT group, in collaboration with the University of Erlangen and Praevium/Thorlabs, has developed a portable instrument that can be taken outside a specialist’s office.
"Hand-held instruments can enable screening a wider population outside the traditional points of care," said researcher James Fujimoto of MIT, an author on the Biomedical Optics Express paper. For instance, they can be used at a primary-care physician's office, a pediatrician's office or even in the developing world.
The researchers were able to shrink what has been typically a large instrument into a portable size by using a MEMS mirror to scan the OCT imaging beam. They tested two designs, one of which is similar to a handheld video camera with a flat-screen display. In their tests, the researchers found that their device can acquire images comparable in quality to conventional table-top OCT instruments used by ophthalmologists.
of the prototype OCT scanner. Both devices acquire 3D OCT images of the retina.
Credit: Biomedical Optics Express
To deal with the motion instability of a hand-held device, the instrument takes multiple 3-D images at high speeds, scanning a particular volume of the eye many times but with different scanning directions. By using multiple 3-D images of the same part of the retina, it is possible to correct for distortions due to motion of the operator’s hand or the subject’s own eye.
The next step, Fujimoto said, is to evaluate the technology in a clinical setting. But the device is still relatively expensive, he added, and before this technology finds its way into doctors' offices or in the field, manufacturers will have to find a way to support or lower its cost.
Many people with eye diseases may not even be aware of them until irreversible vision loss occurs, Fujimoto said. Screening technology is important because many eye diseases should be detected and treated long before any visual symptoms arise. For example, in a 2003 Canadian study of nearly 25,000 people, almost 15 percent were found to have eye disease—even though they showed no visual symptoms and 66.8 percent of them had a best-corrected eyesight of 20/25 or better. Problems with undetected eye disease are exacerbated with the rise of obesity and undiagnosed diabetes, Fujimoto said. The Center for Disease Control and Prevention estimates that 11.3 percent of the U.S. population over the age of 20 has diabetes, even though many do not know it.
In the future, Fujimoto envisions that hand-held OCT technology can be used in many other medical specialties beyond ophthalmology – for example, in applications ranging from surgical guidance to military medicine.
"The hand-held platform allows the diagnosis or screening to be performed in a much wider range of settings,” Fujimoto said. “Developing screening methods that are accessible to the larger population could significantly reduce unnecessary vision loss."
Paper: “Handheld Ultrahigh Speed Swept Source Optical Coherence Tomography Instrument using a MEMS Scanning Mirror,” Lu, C.D. et al., Biomedical Optics Express, Vol. 5, Issue 1, pp. 293-311 (2013).
Source: Biomedical Optics Express via The Optical Society
Thursday, 2 January 2014
DME is a form of diabetic retinopathy, the leading cause of blindness in people with diabetes, and occurs when the blood vessels in the eye's macula - a part of the retina responsible for sharp vision - leak fluid and swell. This can lead to partial vision loss or total blindness. Prompt treatment of the condition can prevent sight loss, but in order to catch the condition early, patients with diabetes need to undergo regular dilated eye examinations.
To determine the awareness of eye care and eye disease among diabetic patients, a team of researchers, led by Dr. Neil M. Bressler of The Johns Hopkins University School of Medicine and Hospital and editor of JAMA Ophthalmology, analyzed 798 participants from the National Health and Nutrition Examination Survey, who had self-reported diabetes. Of these, 238 had diabetic retinopathy without DME, while 48 had DME.
Results of the study revealed that only 44.7% of those with DME said they had been told by their doctor that their eyes had been affected by diabetes, or that they had diabetic retinopathy.
Furthermore, only 46.7% of diabetic individuals with DME said they visited a diabetes nurse educator, dietician or nutritionist for their diabetes more than 1 year ago or never, while only 59.7% said they had a dilated eye exam within the past year.
Commenting on their findings, the researchers said "Our results suggest that many individuals with DME report not receiving prompt diabetes-related or eye-related care, although many of these individuals are at risk of substantial visual loss that could be lessened or eliminated with appropriate care."
This is not the only study to find that diabetic patients lack awareness when it comes to their risk of diabetic eye disease and the importance of regular dilated eye examinations. A recent survey from Diabetic Connect - a social networking site for diabetes sufferers and their families - found that 25% of people with diabetes do not have the recommended annual dilated eye exam.
According to the the National Eye Institute, people with diabetes who undergo a dilated eye exam once a year could reduce their risk of severe vision loss by 95%. The examination involves an ophthalmologist, optometrist or retina specialist putting drops into a patient's eye, which allows them to clearly assess the retina to see whether there is any damage or early signs of disease.
Early detection of diabetic eye disease means the patient can be offered various treatment options to help prevent partial vision loss or blindness. These include laser eye surgery and injections of anti-vascular growth factor (anti-VEGF) medications, which tackle abnormal blood vessel growth in the eye.
The researchers say that although treatment for diabetes-related vision loss has improved, their findings suggest that diabetic patients lack awareness when it comes to their risk of diabetic eye disease, and more effort is needed to educate them in this area.
"These efforts include getting patients to health care providers, including diabetes nurse educators, dieticians, nutritionists, primary care physicians, or endocrinologists, for treatment of their diabetes mellitus; getting appropriate eye examinations to detect and treat diabetic retinopathy, including DME," they note.
They add that strategies should be identified that "might result in greater awareness and appropriate eye care to reduce the magnitude of visual impairment and blindness due to this common complication of diabetes mellitus."
Source: JAMA Ophthalmology via Honor Whiteman, Medical News Today
Thursday, 28 November 2013
The new indication follows results from two clinical trials, in 2007 and 2010, that showed treatment with fenofibrate can prevent progression of early stage DR. There is no evidence, however, that fenofibrate can be used to prevent DR in people with type 2 diabetes or that it can be used has a treatment for people already in the advanced or severe stages of DR.
The first study of 9795 patients showed the need for laser eye surgery in the group that received fenofibrate was reduced by 37%. In the second study of 10,251 people, the need was reduced by 40%.
Anthony Keech, professor of medicine, cardiology and endocrinology at the University of Sydney and principal investigator of the first study, said recent research into the mechanism of the treatment had shown it acted as an anti-VEGF.
Professor Keech said their other research had shown it offered additional benefits that reduced the risk of amputation and seemed to protect against the renal effects of diabetes. He stated that fenofibrate was not intended as a replacement for a statin but as an additional treatment, and had additional benefits for type 2 diabetes patients with mild to moderate DR.
"The current worldwide recommendation is that it be added to statin therapy for people who, if on statins, have elevated levels of triglycerides or lower levels of good cholesterol" he said.
Fenofibrate is not listed on the Australian Pharmaceutical Benefits Scheme for DR, however it is listed for dyslipidaemia associated with type 2 diabetes, making it accessible to 90% of DR patients in Australia.
Source: Medical Observer
Wednesday, 20 November 2013
High-tech medical facilities at a nominal cost, on one's doorstep? It would be but a dream for a large part of India's population. But now a Bangalore-based eye hospital has taken the initiative to provide easy and affordable eye care to diabetics.
Rangalakshmii Netralaya has launched an internet-based, low-cost mobile clinic, which will travel the length and breadth of Karnataka for early intervention to prevent blindness among diabetics.
The clinic was launched on a pilot basis on Bangalore's outskirts on November 14 to coincide with World Diabetes Day. At present, free consultation and medication is being offered to people.
Every mobile clinic is equipped with 3D screening cameras, which capture multi-dimensional images of the eyes. These images are transferred on a real-time basis, using high-speed internet, to specialists at hospitals, who analyse them and offer remedies.
"Diabetic retinopathy is the second largest cause for complete blindness in the world. As India has a highly diabetic population, routine eye screening is a must for every person, especially in villages where awareness is low," said Dr G. Venkatasubramaniam, Medical Director and Vitreo-Retinal Surgeon, Rangalakshmii Netralaya. "This Internet-based mobile clinic has been pioneered to tackle diabetes-related eye ailments in the long term."
India's diabetic population is currently 41 million and could reach 79.4 million by 2030, according to World Health Organisation estimates. It is generally estimated that 15-25 per cent of the diabetic population has diabetic retinopathy, which could cause vision loss if not treated.
So far, Rangalakshmii Netralaya has screened more than 1,500 people in villages around Bangalore and gathered a large amount of data relating to diabetes-related eye ailments.
"If we screen the eyes of a diabetes patient, we will be in a position to foresee what the condition of his kidneys will be over the next 10 years. We are confident that if we start early, we can tackle diabetes effectively. This is essential for a country like India where healthcare services are yet to effectively cover the villages," Dr Venkatasubramaniam added.
Source: Daily Mail
Sunday, 13 October 2013
Scientists from Helmholtz Zentrum München have discovered that metformin treatment normalizes the alterations induced by diabetes in only about half of the altered retinal proteins.
Retinal damage is one of the most common complications of diabetes, and according to the World Health Organization (WHO), diabetic retinopathy is the leading cause of blindness in adults of working age, with its incidence is showing an upward trend.
The retina is the part of the eye that converts optical images into nerve signals, which are then transmitted to the brain where vision is interpreted. Numerous proteins and molecules are involved in the process of signal transduction. Diabetic retinal damage leads to impaired function of these proteins.
Within the framework of research projects of the German Center for Diabetes Research (DZD), scientists of the Research Unit Protein Science (PROT) and the Institute of Experimental Genetics (IEG) at Helmholtz Zentrum München (HMGU) have now investigated how drug treatment affects these signal carriers. They compared the concentrations of proteins in the retinas of non-diabetic mice, of mice with type 2 diabetes without treatment and of type 2 diabetic mice that were treated with the standard drug metformin, which lowers blood glucose levels and thus reduces diabetes complications.
A total of 98 proteins were deferentially abundant in the diabetic animals. About half of the proteins were normalized by treatment with metformin. The other proteins were unchanged, however, despite treatment and improved blood glucose levels. Among these was the protein VGLUT1, which is essential for signal transduction in specific nerve cells.
"Our results show that normalized blood glucose levels alone are not sufficient to fully treat diabetic retinopathy," said Dr. Alice Ly, PROT scientist and lead author of the study.
"In further studies we want to examine how different combination therapies affect the retinal proteins, in order to achieve a better understanding of the causes and treatment of this diabetes complication," added Dr. Stefanie Hauck, also a PROT researcher.
Source: Diabetologia via Helmholtz Zentrum München
Thursday, 10 October 2013
"Diabetic retinopathy is first cause of blindness in people aged 50 years or less in industrialized countries. In addition to well-recognized risk factors, such as duration of diabetes, poor glycemic and blood pressure control, excess visceral fat has been suggested to play a role by some studies," Dr Dossarps stated.
Adipose tissue secretes specific hormones, the adipokines. Obesity modifies adipokine secretion by decreasing adiponectin and increasing leptin, he explained.
"Adiponectin improves insulin sensitivity and decreases arteriosclerosis and neovascularization, while leptin decreases insulin sensitivity, regulates appetite and promotes neovascularization," said Dr Dossarps.
The study analysed 179 patients with type 2 diabetes. Measurement of visceral and subcutaneous fat by MRI and measurement of serum adiponectin and leptin were taken. Assessment of diabetic nephropathy was performed.
"We used the AAO classification to grade the severity of DR (diabetic retinopathy) and divided patients in 3 groups according to absence of DR, simple DR or advanced DR. A total of 69 patients were found to have DR," Dossarps said.
No significant difference was found in the 3 groups in relation to visceral or subcutaneous fat, as well as levels of adiponectin and leptin, leading to the conclusion that no association could be made in the study between abdominal fat or adipokine secretion and diabetic retinopathy.
Source: EURETINA via Healio
Friday, 20 September 2013
For example, the mean levels of products of lipid peroxidation such as malondialdehyde and 4-hydroxyalkenals were 1.42 µmol/L in patients with mild diabetic retinopathy compared with 0.98 µmol/L in healthy controls, according to Alejandra Guillermina Miranda-Diaz, MD, PhD, of the University of Guadalajara in Mexico, and colleagues, while in those with moderate and severe retinal involvement, levels rose to 2.49 µmol/L and 3.29 µmol/L (P<0.017), respectively. "Because [lipid peroxidation] is a well established mechanism of cellular lesions, these findings suggest cellular and systemic oxidative stress," Miranda-Diaz and colleagues observed.
Hyperglycemia in diabetes can lead to death of vascular cells and neurons in the retina, through various mechanisms such as the conversion of reactive oxygen species to hydrogen peroxide and singlet oxygen, which then can lead to lipid peroxidation. "Chronic hyperglycemia alters the homeostasis of vascular endothelial cells and causes changes in the expression of genes that incite [diabetic retinopathy], favoring early functional changes that augment the permeability of the basal membrane of the retina, with endothelial cell dysfunction and increased oxidative stress," they explained.
Nitric oxide also contributes through the oxidation of nitric oxide synthase and the production of reactive nitrogen species. In addition, mitochondrial dysfunction can further accelerate retinal apoptosis through morphologic disturbances.
To quantify these changes and their ocular effects in diabetes, the researchers enrolled 270 adult patients who had not been diagnosed with diabetic retinopathy along with age- and sex-matched nondiabetic controls.
They identified 12 patients with mild, 18 with moderate, and 30 with severe non-proliferative diabetic retinopathy.
Mean age of affected patients was about 60, and mean duration of diabetes was 15 years.
Mean hemoglobin (Hb) A1c levels were 8.21%, 8.98%, and 9% in the mild, moderate, and severe groups, respectively.
Glucose levels also were high, at 123.66 mg/dL, 148.77 mg/dL, and 142 mg/dL in the three groups, as were levels of total cholesterol, at 167.41, 199.66, and 202.81 mg/dL.
Among healthy controls, levels of nitric oxide catabolites averaged 12.31 pmol/mL. But in patients with mild, moderate, or severe retinopathy, the levels were 25.32 pmol/mL, 36.56 pmol/and 45.62 pmol/mL (P<0.0001), suggesting the presence of nitrosative stress, according to the researchers. Aside from these pro-oxidant factors, abnormalities also were seen in patients' antioxidant profiles that correlated with worsening control of metabolic processes. Compared with uric acid values of 22.41 mEq/mL (representing total antioxidant capacity) in healthy individuals, levels decreased to 16.05 mEq/mL, 12.90 mEq/mL, and 7.98 mEq/mL in patients with mild, moderate, and severe retinopathy. "Uric acid has antioxidant activity by participating in the detoxification of lipid hydroperoxides into nontoxic alcohols," they wrote.
Catalase and glutathione peroxidase activity also increased with worsening retinopathy. For erythrocyte catalase activity, levels were 142.12, 136.45, and 139.40 U/mg protein in the mild, moderate, and severe groups (P<0.0001), while levels of glutathione peroxidase activity were 100.21, 95.32, and 117.13 U/min/mg protein (P<0.0001). "It is possible that the greater catalase and [glutathione peroxidase] activity in nonproliferative [diabetic retinopathy] could be due to a compensatory response to the oxidative stress caused by a persistent metabolic disorder," the researchers suggested.
They then looked at mitochondrial function, measuring the fluidity of platelet mitochondrial membranes, and found that the fluorescence ratio of excimer to monomer was low in patients with all levels of retinopathy (P<0.0001). "The decrease in fluidity compared with the control group could be related to the effect that the fluidity of the membrane has on membrane potential induced by the increase in HbA1c, dyslipidemia, oxidative stress, or their combination," the researchers explained.
Alterations in mitochondrial membranes have also been observed in Alzheimer's disease.
The research team also detected increases in the hydrolytic activity of mitochondrial ATP, which "could mean lower ATP synthesis with excessive production of cellular catabolism."
These findings could have implications for monitoring and treatment, they noted. For instance, periodic measurement of levels of products of lipid peroxidation could provide an early signal of incipient retinopathy, and the administration of antioxidants might help counteract oxidative stress.
"We believe that understanding the distinct molecular mechanisms responsible for mitochondrial damage could help identify management alternatives to postpone or prevent the [diabetic retinopathy] that threatens the vision of people who suffer from [diabetes mellitus]," they concluded.
Source: Journal of Diabetes via Nancy Walsh, MedPage Today
Thursday, 19 September 2013
At 36-month follow-up, vision and the severity of diabetic retinopathy were significantly more likely to have improved in patients treated with monthly ranibizumab (also known as Lucentis) than in those treated with a sham injection. In addition, ranibizumab-treated patients were approximately 3-fold less likely to develop proliferative diabetic retinopathy than their sham counterparts.
The results were presented by Lloyd Clark, MD, from the Palmetto Retina Center in West Columbia, South Carolina, at the 31st Annual Meeting of the American Society of Retina Specialists, and reported by Medscape Medical News.
"It's difficult to extrapolate the data from these studies strictly to the real-world situation because patients in these trials received monthly injections of ranibizumab for 3 years, and that is a difficult regimen to follow in the clinic," Dr. Clark told Medscape Medical News. "But the findings are very encouraging, in that they show that when used in combination with conventional modalities, [anti-VEGF] treatment can improve diabetic retinopathy in these patients," he added.
In the phase 3 RISE and RIDE trials, patients with diabetic macular edema were randomly assigned to ranibizumab — either 0.3 mg or 0.5 mg monthly — or sham injections. At baseline, best-corrected visual acuity ranged from 20/40 to 20/320, and central subfield thickness on optical coherence tomography was at least 275 µm. The primary end points of the trial were change in best-corrected visual acuity, change in the severity of diabetic retinopathy at month 24, and the effect of treatment on worsening diabetic retinopathy at month 24.
At month 24, patients who had previously received sham injections were crossed over to ranibizumab 0.5 mg monthly. "Ranibizumab improved vision in diabetic macular edema patients through 36 months," Dr. Clark observed. At month 24, mean change in best-corrected visual acuity, based on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, was 11.7 to 12.0 letters for the 2 ranibizumab groups, and was 2.5 letters for the sham injection group.
After crossover from sham injections to monthly ranibizumab, the mean change in best-corrected visual acuity remained relatively stable for the 2 ranibizumab groups and improved by a mean of 4.5 letters for the sham injection group.
The severity of diabetic retinopathy was also significantly more likely to improve with either dose of ranibizumab than with sham injection.
"These data suggest that improvement in retinopathy occurs early in the course of ranibizumab therapy," Dr. Clark noted. The severity of diabetic retinopathy was also significantly less likely to worsen in patients treated with ranibizumab than in those treated with sham injections, he added.
At 36 months, 33.9% of eyes originally assigned to sham injections developed proliferative diabetic retinopathy, despite crossing over to monthly ranibizumab at month 24.
In contrast, only 12.8% of eyes treated with the 0.3 mg dose of ranibizumab and 15.1% of those treated with the 0.5 mg dose had evidence of proliferative disease at month 36. When sham eyes crossed over to active therapy, the rate of proliferative diabetic retinopathy did slow.
However, Dr. Clark noted, many of the eyes that worsened in the third year had developed proliferative disease by month 24, and they remained classified as proliferative diabetic retinopathy at the end of the trial.
"Due to the size and duration of RISE and RIDE, we had a unique opportunity to understand risk factors for diabetic retinopathy progression," Dr. Clark explained.
In the sham group, at month 24, more severe diabetic retinopathy (hazard ratio [HR], 0.24) and the presence of subretinal fluid on optical coherence tomography at baseline (HR, 0.52) were strongly and significantly related to the risk of developing proliferative diabetic retinopathy.
In contrast, capillary loss in the macular grid at baseline was strongly and significantly related to the development of proliferative diabetic retinopathy in the ranibizumab groups, compared with no capillary loss (HR, 0.41). In the overall cohort, treatment with ranibizumab was the factor most significantly associated with a reduced risk for progression of diabetic retinopathy (P < .0001 for both doses). "A small percent of eyes still progress to proliferative diabetic retinopathy, despite monthly ranibizumab," Dr. Clark said. "And while I don't think these numbers suggest a paradigm shift in our practice yet, they certainly demonstrate encouraging results from VEGF suppression in proliferative diabetic retinopathy."
"I think these results are absolutely fascinating," said Suber Huang, MD, professor of ophthalmology at Case Western Reserve University School of Medicine in Cleveland, who was asked by Medscape Medical News to comment on the findings. "Dr. Clark and his study group should be congratulated on their results."
Source: American Society of Retina Specialists via Medscape Medical News