Empagliflozin was associated with a 22 per cent lower risk of progression from early stages of diabetic retinopathy to more advanced stages in this patient group.
Diabetic retinopathy (DR) affects about 26 per cent of people with diabetes. While many patients have an early form of DR, the condition can progress, posing the threat of irreversible vision loss. Empagliflozin is a sodium-glucose contratransporter-2 inhibitor (SGLT-2), an oral medication that helps patients with type 2 diabetes control their glucose levels. A research team led by investigators from Mass General Brigham conducted a cohort study comparing treatment with empagliflozin to another form of diabetes treatment for patients with type 2 diabetes. They found that while empagliflozin did not reduce the risk of DR in patients with no history of that disease, among patients who had early-stage DR, the medication was associated with a decreased risk of progression.
“Our findings showed that in patients with type 2 diabetes and non-proliferative diabetic retinopathy, empagliflozin could be beneficial in slowing down progression to more advanced stages of diabetic retinopathy,” said lead author Helen Tesfaye, PharmD, MSc, of the Division of Pharmacoepidemiology at Brigham and Women’s Hospital. “Our findings could help inform clinical decision-making for patients with diabetes who have non-proliferative diabetic retinopathy or are at risk for developing DR.”
The study represents a collaboration between Brigham and Women’s Hospital (BWH) and Massachusetts General Hospital (MGH), both founding members of the Mass General Brigham healthcare system, with experts from BWH’s Division of Renal (Kidney) Medicine and MGH’s Diabetes Center working with Tesfaye and colleagues from the Division of Pharmacoepidemiology.
“Leveraging the clinical and analytical expertise of our multidisciplinary team allows us to identify risks and benefits of diabetes medications that are not being studied—or may not be apparent—in clinical trials,” said Deborah Wexler.
Patients with diabetes face a host of potential health problems as they work to manage the chronic disease. Still, one concern that seems to weigh heavily is the risk of losing their sight through a condition known as diabetic retinopathy.
Researchers at the University of Oklahoma Health Sciences and Memorial Sloan Kettering (MSK) Cancer Center are studying a new, revolutionary treatment for diabetic retinopathy that could change the prognosis for these patients. Julia Busik, Ph.D., professor and chair of the department of biochemistry and physiology in collaboration with Richard Kolesnick, MD of MSK Cancer Center, recently published a paper in the journal Cell Metabolism that details how anti-ceramide immunotherapy can address the root cause of the disease and stop progression toward blindness at an earlier stage than previous treatments.
“With the rise in diabetes, there’s a rise in complications. One-third of adults over age 40 with diabetes have retinopathy,” said Busik. “If left untreated, diabetic retinopathy can lead to blindness. Losing vision is one of the most feared complications for patients with diabetes.”
This blindness is caused by hemorrhaging lipid, or fatty compound, build-ups. These start as dark spots in the field of view but can, as they multiply, become vision-threatening and eventually cause blindness. There are currently two treatments for diabetic retinopathy, but both have serious health implications and are fairly invasive. One involves lasers that burn the vessels to stop the hemorrhaging; another involves injections directly into the eye that can stop the progression of the disease. According to Busik, these treatments are only sometimes effective.
The researchers are working on an exciting new treatment that could address the root cause of diabetic retinopathy. Continuing research that she began at Michigan State University, Busik has taken a closer look at lipids, specifically lipid pathways in the retina of the eye, and how they are affected by diabetes. She and her team found that a certain, very damaging type of lipid, or ceramide, was present in the eyes of patients with diabetic retinopathy. In turn, they discovered that these ceramides, after stimulation by another type of cell – cytokines – stick together into large domains that cause damaging inflammatory signals to cells in the eye. This causes cell death and the progression of diabetic retinopathy.
In collaboration with the Kolesnick laboratory at MSK Cancer Center, Busik’s team was then able to create an antibody against these lipids to prevent the ceramide buildup from happening and signaling the damage to healthy cells in the retina. The studies show great promise in animal and cell culture models.
Perhaps the most important advance from the current treatment is that it addresses the root cause of the disease, as opposed to late symptoms and stopping progression at the vision-threatening stage, explains Busik. It can also be administered systemically, so it does not have to be injected into the eye. Due to their invasive nature and safety concerns, currently available treatments are only used at very late stages of the disease when the vision is threatened.
“If we have this systemic safe treatment,” said Busik. “It could be given to a patient at a much earlier stage when they are just starting to progress, to make sure that they never get to that late stage.”
Cells within retinal blood vessels are endowed with a previously unappreciated ability to acquire resistance against the damaging effects of hyperglycemia in patients with diabetes mellitus, researchers report in The American Journal of Pathology
Culturing primary human retinal endothelial cells under hyperglycemic conditions initially compromised their mitochondria. The cells respond by adapting, which includes clearance of the dysfunctional mitochondria via mitophagy. Such adaptation is a plausible contributor to the underlying mechanism responsible for the long delay between the onset of diabetes and the manifestation of diabetic retinopathy. Furthermore, loss of adaptation may be a prerequisite for the development of retinopathy in patients with diabetes. CREDIT The American Journal of Pathology
About one third of patients with diabetes mellitus (DM) develop diabetic retinopathy (DR), a leading cause of blindness in working-age individuals. DR typically develops after many years of DM, and some patients do not develop DR for more than 50 years. New research suggests that an endogenous system that protects human retinal endothelial cells from harmful effects of the hyperglycemia (an excess of blood sugar) may be responsible for the delayed onset of DR. Furthermore, degradation of this protective system over time may set the stage for development of DR. The new study appears in The American Journal of Pathology, published by Elsevier.
“The prevailing understanding of what causes DR predicts that it will develop soon after the onset of DM,” explained lead investigator Andrius Kazlauskas, PhD, Departments of Ophthalmology and Visual Sciences and Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA. “Yet this is not the case. Although the long delay from the onset of DM to the development of DR is a well-known clinical phenomenon, there is relatively little effort to investigate the underlying reason for this delay. Uncovering this information constitutes an exciting opportunity to improve current approaches to prevent DM from progressing to DR.”
Exposing cultured cells, such as vascular endothelial cells, to high glucose is a common in vitro model of DR. The investigators cultured human retinal endothelial cells in either normal glucose or high glucose–containing media. Unexpectedly, they found that prolonged exposure to high glucose was beneficial, not detrimental. After one day, the health of the cells declined, but as the duration of exposure was prolonged, the cells recovered and acquired resistance to DM-related damage such as inflammation and death.
The investigators found that the adaptation was associated with improved mitochondria functionality. Mitophagy is the process in which cells remove damaged mitochondria, and disruption of this intrinsic quality control system is associated with many diseases. Though initially compromised, mitochondrial functionality was improved after 10 days of exposure to high glucose, with increased clearance of damaged mitochondria. Interfering with the mitochondrial dynamics compromised the cells’ ability to endure high glucose. Susceptibility to cell death increased, and responsiveness of vascular endothelial growth factor deteriorated.
Dr. Kazlauskas said these observations indicate the existence of an endogenous system that protects human retinal endothelial cells from the deleterious effects of hyperglycemia. “The compelling role of mitochondrial dysfunction in the development of DR supports our central concept of a hyperglycemia-induced mitochondrial adaptation (HIMA) system, the purpose of which is to preserve the functionality of mitochondria. We posit that the loss of HIMA sets the stage for advancing to DR.”
An important component of the HIMA concept is that improving the functionality of a subset of retinal cells will be beneficial for the whole retina. Previous research has found even a small reduction in degree or type of insult to the retina can protect animals that have DM from developing DR. Together these discoveries suggest that the development of DR involves a relatively small shift in the balance between exogenous insults and the endogenous systems that prevent DM-driven damage and drivers of pathogenesis.
Dr. Kazlauskas observed that the increasing incidence of DM, and consequently of DR, around the world exacerbates the need for effective approaches to protect patients from this serious complication. “Does HIMA exist in vivo, does it protect patients from DR, and is its demise a prerequisite for progression to DR? Our ongoing research is focused on answering these open questions,” he concluded.
A: Multicolor widefield SLO image of the right fundus of a 65-year-old man with PDR showing multiple hemorrhages in a wide area of the fundus. B: Blue SLO image shows a hyporeflective area in the mid-periphery to periphery of the fundus. C: Widefield FA image shows widespread NPAs in the mid-periphery to periphery. Neovascularization is also seen in the superior pole of the eye. D: Magnified image of image B shows hyporeflective areas in the lower temporal quadrant. E: Magnified FA image of image C shows NPAs in the same quadrant of image D. F: The hyporeflective areas in image D are outlined by white dots. G: The NPAs in image E are outlined by blue dots. The outline of white dots in image F is located inside the outline of blue dots image G. (Horie S, Ohno-Matsui K et al. Asia Pac J Ophthalmol (Phila). 2021 Aug 27; 10(5):478-485) CREDIT Department of Ophthalmology and Visual Science, TMDU
Just as bright light can illuminate the depths of a darkened room, researchers in Japan have found that blue light can be used to probe the depths of the eye and uncover areas affected by diabetic retinopathy (DR), a leading cause of blindness.
In a new study published in Asia-Pacific Journal of Ophthalmology, researchers from Tokyo Medical and Dental University (TMDU) have revealed that blue images obtained by multicolor widefield scanning laser ophthalmoscopy (SLO) may be used to identify areas of DR-induced damage in a more extensive portion of the eye compared with previous methods.
Current eye imaging methods include fluorescein angiogram, which involves the injection of dye into the eye. SLO is a non-invasive approach that does not require dye, and multicolor widefield SLO represents an advancement of this technique in which red, blue, and green lasers are used to simultaneously capture images of a wide portion of the eye. Previous research has shown that blue images captured by conventional SLO may reveal hyporeflective areas in the eye indicative of damage associated with DR. Researchers at TMDU sought to further evaluate this finding using widefield SLO.
In this retrospective study, the researchers compared blue widefield SLO images and fluorescein angiogram images taken in people with diabetes. The morphology of the retina was also evaluated in some individuals with DR.
“We found that the hyporeflective areas in the blue widefield SLO images appeared to correspond with areas of ischemia in the fluorescein angiogram images of patients with DR,” explains Kyoko Ohno-Matsui, senior author. “We were pleased to find that the rate of concordance was high.”
Further evaluation of patient images showed that ischemic areas (i.e., areas of reduced blood flow) appeared to correspond with parts of the retina that were thin and partially disorganized.
“It’s possible that the blue wavelength of light can pass more easily through these thinned areas of the retina, which presents as hyporeflective areas in the SLO images,” says Horie.
This study confirms the utility of blue widefield SLO as a simple and non-invasive tool for the detection of DR-associated damage in the eye. This technique may serve as an important means of screening and monitoring disease progression in individuals with DR.
A complication of diabetes that affects the eyes. It’s caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina).
The four stages of diabetic retinopathy include:
1. Mild Nonproliferative Retinopathy. This beginning stage is often where swelling begins in the retina’s blood vessels. …
2. Moderate Nonproliferative Retinopathy.
3. Severe Nonproliferative Retinopathy.
4. Proliferative Retinopathy. Early symptoms include floaters, blurriness, dark areas of vision and difficulty perceiving colours. Blindness can occur.
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