Objective
The primary objective of this study is to determine if treatment with fenofibrate is effective at preventing diabetic retinopathy (DR) worsening in individuals with mild to moderately severe non-proliferative DR (NPDR) at baseline. If fenofibrate is demonstrated to be effective, then additional study goals are to provide a model for ophthalmologists to prescribe and/or collaborate with internists to prescribe and monitor fenofibrate in diabetic patients safely and to disseminate standardized guidelines for prescribing this treatment to encourage broader use. This study will also give information on whether variation in blood sugar control is a risk factor for future worsening of diabetic eye disease. In addition to the objectives above, this study will enroll a large group of participants with DR in which contemporary information on natural history can be collected.
Background Rationale
Despite advances in diagnosis and management of eye disease in patients with diabetes, diabetic retinopathy continues to be one of the leading causes of vision loss and new onset of blindness in working-age individuals throughout the United States and other developed countries worldwide. Currently, the primary method of preventing diabetic retinopathy (DR) onset and worsening remains that of strict control of blood sugar. However, despite patients’ best efforts to follow control guidelines, most diabetes patients will develop DR after 10 – 20 years of diabetes and many will be at severe risk of vision loss from DR worsening over the subsequent years. Current best treatments for late-stage, vision-threatening DR, while highly effective, are also invasive or destructive, require frequent treatments that can be costly and have well-documented potential associated complications. In addition, not all eyes respond to these standard treatments. Thus, there is an ongoing need to identify new therapies that can prevent the progression of diabetic eye disease in order to lessen the risk of future vision loss and treatment burden associated with advanced DR.
Fenofibrate is an affordable, readily available oral medication that has already been demonstrated to have favorable effects in preventing DR worsening in secondary analyses of prior studies enrolling type 2 diabetes patients. A larger study could confirm these results as well as provide outcomes from participants with type 1 diabetes that are not yet available. A study conducted by the DRCR Retina Network, if definitively demonstrating fenofibrate as safe and effective for prevention of DR worsening, will help facilitate the increased use of this therapy in the retina community and could have substantial, public health impact on type 1 diabetes patients with retinopathy worldwide.
Description of Project
Despite improved glycemic and systemic control for many patients over the past several decades, diabetic retinopathy (DR) develops and progresses in a large proportion of patients with diabetes, and visual loss from diabetic complications continues to be a leading cause of blindness in the US and other developed countries worldwide. Thus, even a modest ability to prevent DR onset or to slow DR worsening might substantially reduce the number of patients at risk for diabetes-related vision loss worldwide. Identification of an affordable, safe and readily available oral medication that prevents DR worsening would allow treatment of wider segments of the diabetic population at risk for diabetic eye complications but without access to current therapies such as injections of medications into the eye or laser treatment, as well as those who are not suitable candidates for such therapies. Widespread use of an effective oral medication might also decrease the number of patients who need to undergo these invasive or destructive treatments and who are consequently at risk for side effects like loss of vision.
Prior clinical studies have shown that fenofibrate can reduce risk of DR worsening in type 2 diabetes patients in a subgroup of participants with mild to moderate DR. However, a definitive trial specifically in eyes with baseline levels of diabetic eye disease is necessary to confirm these results. Treatment with fenofibrate has not been adopted by the retina community, perhaps due to lack of communication and established mechanisms for coordinating the prescription of fenofibrate with primary care providers resulting in uncertainty as to how to best monitor patients on fenofibrate for rare systemic complications such as liver and muscle damage. The results from a study designed specifically for retina specialists to evaluate the effects of fenofibrate on DR, if positive, might have better opportunity to permeate into the community and affect change in practice patterns in a way that would benefit patients.
In addition, by conducting this study in the DRCR Retina Network, over 300 retina specialists will gain experience using fenofibrate for this indication, which may help permeate fenofibrate into practice if treatment is successful on this trial. This study has the potential to have a major and positive impact on public health if it definitively identifies fenofibrate as an effective prevention for DR worsening in a large cohort of patients with both type 1 and type 2 diabetes, as well as providing guidance to physicians for its implementation into clinical care. Through the use of continuous glucose monitoring in the study group, this trial will also address an additional important question as to whether or not blood sugar variability is a risk factor for worsening of diabetic eye disease. Thus, this study will expand our understanding of the role of hyperglycemia in diabetic eye complications. The large untreated cohort will allow for assessment of many factors that may be important in understanding the progression of diabetic retinopathy.
Anticipated Outcome
This DRCR Retina Network-sponsored study will assess the safety and effectiveness of fenofibrate versus placebo treatment for the prevention of diabetic retinopathy (DR) worsening in eyes with mild to moderately severe non-proliferative DR (NPDR) over 4 years. The DRCR Retina Network has designed, implemented, and reported results from 22 successful multi-center clinical trials over the last 18 years, many of which have been instrumental in setting the current standards of care for diabetic eye disease. As such, we anticipate that this study will be similarly enrolled and conducted efficiently and effectively, with focused effort on study participant retention throughout the 4 years of scheduled follow-up. Given prior sub-studies have demonstrated the benefit of fenofibrate in prevention of DR worsening with type 2 diabetes patients, we likewise expect that participants randomized to fenofibrate treatment in this study will have decreased rates of DR worsening as compared to those of the placebo group. Furthermore, given our long collective experience with fenofibrate use and low rates of fenofibrate-associated complications, we anticipate that this treatment will be well-tolerated by study participants. We predict that patients with shorter and less frequent intervals of well controlled blood sugar will be more likely to experience DR worsening over time. If these hypotheses are correct, results from this proposed study could set a new standard of care for prevention of worsening of diabetic eye complications and vision loss in patients with type 1 diabetes. The DRCR Retina Network would then be able to provide guidance to ophthalmologists for implementation of this therapy in the community, which are currently lacking.
Relevance to T1D
Despite improved control of blood sugar, high blood pressure and blood cholesterol levels for many patients over the past several decades, individuals with type 1 diabetes are at increasing risk for vision loss from advanced diabetic eye complications as they survive longer durations of diabetes. One study found that nearly 50% of patients developed vision threatening diabetic retinopathy after living 15 years with this chronic disease. The goal of this study is to evaluate whether treatment with fenofibrate is safe and effective in preventing DR worsening. The study will also evaluate whether variability of blood sugar control affects DR worsening. Since diabetic retinal abnormalities are the most common cause of vision loss in patients with type 1 diabetes, the results from this study are highly relevant to this group of individuals. If this study demonstrates that fenofibrate is effective and safe for reducing advanced diabetic eye complications and the results are adopted by the retinal community, a new strategy to prevent vision threatening complications of diabetes will be available for patients with type 1 diabetes worldwide.