DIABETIC RETINOPATHY UPDATE
Year : 2013 | Volume
: 20 | Issue : 4 | Page : 309--314
Should we start all patients with diabetic retinopathy on fenofibrates?
Jacob Koshy1, Jency M Koshy2, Satish Thomas1, Gurvinder Kaur1, Thomas Mathew1,
1 Department of Ophthalmology, Christian Medical College, Ludhiana, Punjab, India
2 Department of Medicine, Christian Medical College, Ludhiana, Punjab, India
Department of Ophthalmology, Christian Medical College, Ludhiana - 141 008, Punjab
There remains a need for strategies that are effective in preventing diabetic retinopathy (DR) or slowing down its progression, which is safe, well-tolerated, and more effective, have a lower risk profile, easy to perform, have more predictable results with less morbidity than the current regimens. Physicians caring for diabetic patients not only need to maximize glycemic control, but also closely monitor and treat other systemic conditions. The consistency of clinical data from the fenofibrate studies showed consistent beneficial effects with fenofibrate in slowing the progression of DR. They demonstrated significant benefit on micro-vascular (i.e., retinopathy and nephropathy) outcome, possibly independent of lipid levels. Can we combine the effectiveness of the current standard procedures with the prevention and slowing down of progression of DR that fenofibrates can offer? Knowledge of the primary mode of action of fenofibrate will be useful for both physicians and patients in determining how best to use this drug as an adjunct in the management of DR and ultimately facilitating the translation of clinical trial data to clinical practice.
|How to cite this article:|
Koshy J, Koshy JM, Thomas S, Kaur G, Mathew T. Should we start all patients with diabetic retinopathy on fenofibrates?.Middle East Afr J Ophthalmol 2013;20:309-314
|How to cite this URL:|
Koshy J, Koshy JM, Thomas S, Kaur G, Mathew T. Should we start all patients with diabetic retinopathy on fenofibrates?. Middle East Afr J Ophthalmol [serial online] 2013 [cited 2019 Dec 6 ];20:309-314
Available from: http://www.meajo.org/text.asp?2013/20/4/309/120012
Diabetes mellitus (DM) is the most prevalent metabolic and probably the most important of the non-communicable diseases. The micro-vascular and macro-vascular complications have a significant impact on the quality-of-life and increase in the morbidity and mortality of these patients. This global epidemic is largely due to population growth, aging, urbanization and the scourge of obesity and physical inactivity. The total number of people world-wide with type 2 diabetes was expected to increase from 171 million in 2000 to 366 million in 2030.  Unfortunately, the prevalence world-wide already reached 366 million by 2011 according to the International Diabetes Federation and the projections are that the prevalence of diabetes on a global scale could well reach 530 million people in 2030.  Of the diabetics, about one in three has signs of diabetic retinopathy (DR) and 1 in 10 has vision-threatening complications, including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).  PDR remains the leading cause of blindness among working age individuals in developed countries. , DR generally remains asymptomatic until visual loss develops. Even if many people with diabetes may not develop vision-threatening stages of DR in the short-term, , it is likely that an increase in the number and longevity of people with diabetes will substantially impact the public health burden of DR over time.
Unlike a patient with cataract where one procedure like phacoemulsification can rectify the problem, with DR patients, there is not yet one single medication or procedure that can resolve all the potential manifestations of the disease. Good glycemic control is recommended to prevent the progression of diabetes. These goals are sometimes difficult to achieve and consequently DR develops. Though there have been effective treatments for vision-threatening retinopathy, these have well-recognized limitations. This discussion includes a review of the recent studies, including the fenofibrate intervention and event lowering in diabetes (FIELD)  study and action to control cardiovascular risk in diabetes (ACCORD)-eye,  a sub-study of the National Institutes of Health-funded ACCORD study, on the standard treatment of DR and its limitations, suggesting the role and advantages of fenofibrates in DR.
Standard Pharmacological Treatment of Diabetes and its Co-Morbidities
The principal aim in prevention of DR is the optimal control of hyperglycemia. The landmark diabetes control and complications trial has shown that intensive therapy delays the onset and slows the progression of DR, nephropathy and neuropathy in patients with insulin dependent DM. , Studies , have shown that every 1% absolute reduction in hemoglobin A1c (HbA 1 c) produces approximately 35% reduction in the onset of retinopathy and rates of significant progression. Though, the magnitude of absolute risk reduction declines with continuing proportional reduction in HbA 1 c; there is still a meaningful reduction in risk as the level is reduced toward the normal range. The steno-2 trial, a multifactorial intervention strategy, targeting treatment goals similar to those recommended in the American Diabetes Association guidelines resulted in 58% reduction in the risk of DR in type 2 DM (T2DM) patients after 8 years.  Despite this, about one-third of patients receiving intensive multifactorial intervention still developed DR. Furthermore, while the beneficial effects of a multifactorial intervention persisted for the next 5 years, it is worth noting that about half of the patients showed DR progression.  There have been attempts to determine whether a more aggressive approach to risk factor control might confer additional benefit. However, while further intensive control targeting normoglycemia (HbA 1 c < 6.5%) offers additional benefit compared with standard care,  the lack of cardiovascular benefits and increased mortality associated with this approach questions its suitability. 
Lowering high blood pressure significantly reduces the development and progression of retinopathy and macular edema in both type 1 and type 2 diabetic patients. , Modest elevations of either systolic or diastolic blood pressure that may be within the normal range for non-diabetic people, significantly increase the risk for development and progression of retinopathy compared with diabetic patients with lower blood pressures.  The United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive blood pressure control versus standard control achieved a significant reduction in the progression of DR.  With regard to blood pressure, trials suggest that there may be a "floor" effect, with no further benefit on DR progression with more intensive blood pressure control beyond what was observed in the landmark UKPDS. ,,
Anemia is thought to exacerbate the ischemic aspect of DR.  In a cross-sectional study of diabetic patients, those whose hemoglobin levels were lower than 12 g/dl had a two-fold higher prevalence of retinopathy after other known factors were controlled for.  It was also found that in patients with retinopathy, the severity correlated with the severity of anaemia.  The early treatment diabetic retinopathy study (ETDRS) studied the effect of moderate levels of anemia. A low hematocrit was an independent risk factor for high risk proliferative retinopathy and severe vision loss.  Treatment of anemia may result in a slowing of the progression of capillary non perfusion and the development and of proliferative retinopathy. 
Micro-albuminuria and anemia have been found to be strong predictors for DR, clinically significant macular edema and hard exudate formation in type 2 diabetics even after correcting for the duration of diabetes and other systemic risk factors.  In type 2 diabetes, micro-albuminuria may not only be a marker of renal disease, but also have a close association with generalized cardiovascular disease, increasing the risk of myocardial infarction or stroke.  Singh et al. found that increasing albuminuria was significantly associated with PDR.  Larger cross-sectional studies have concluded that micro-albuminuria is a reliable marker for DR. ,
Early angiotensin receptor blockade appears to be of benefit in patients with T1DM. In the renin-angiotensin system study, treatment with either enalapril or losartan reduced DR progression by 65% (P = 0.02) and 70% (P = 0.008), respectively.  In addition, in the DR candesartan trials program, candesartan reduced the incidence of DR in patients with T1DM (by 26%, P = 0.046).  However, candesartan treatment did not arrest the progression of DR in patients with T2DM, although significant regression of DR was detected in patients with mild DR. 
Lipids may independently contribute to the micro-vascular injury in diabetes.  In particular, oxidized LDL has been shown to stimulate inflammation and fibrogenesis through the promotion of cytokine production.  The multi-center ETDRS reported a relationship between total and low density lipoproteins (LDLs) and the frequency of retinal hard exudates.  Reports of intensive treatments with statins associated with hypertension control did result in a decrease in intraretinal hard exudates.  However, once lipid exudates have collected within the fovea, vision does not improve even if the exudates resolve with treatment.  Treatment approaches specifically targeting dyslipidemia (e.g., statins) have not shown any significant benefits for DR. ,
Newer modalities of treatment
Newer pharmacological treatments for DR are needed. Very few studies are testing new drugs in DR due to the necessity of long-term studies on large cohorts and the need for retinal photographs evaluated by standardized masked grading. The need for a lengthy trial also seems to be a factor to separate the intervention and control groups. Most of the efforts also target stopping or slowing down progression rather than on prevention of DR. Some of the newer modalities being evaluated are angiotensin receptor blockers and peroxisome proliferator activated-receptor alpha (PPARα) agonists.
Fenofibrate is a peroxisome PPARα agonist. Recently, two major prospective randomized controlled trials have indicated potential for fenofibrate, in preventing or arresting the progression of DR in patients with diabetes. The FIELD  study and the ACCORD-eye,  showed consistent beneficial effects with fenofibrate in slowing the progression of DR.
The Role of Fenofibrates in DR
The FIELD study  was a placebo-controlled trial primarily designed to assess the effects of fenofibrate on cardiovascular outcomes. Overall, 9795 patients were included, of whom 4895 received fenofibrate. None of the patients received a statin at baseline. It also assessed whether long-term therapy with fenofibrates could reduce the need for laser treatment. Among 814 patients (8%) with DR at baseline, 3.6% of patients treated with fenofibrate versus 5.2% in the placebo group required laser therapy over 5 years (P = 0.0003). Fenofibrate treatment (at a dose of 200 mg/day) reduced the frequency of laser treatment for macular edema by 31% and PDR by 30%.  The FIELD study also incorporated an ophthalmology sub-study in which standardized fundus photographs were routinely taken.  In this sub-study, 1012 patients without evidence of clinically significant retinopathy (proliferative or severe non-proliferative disease), DME or history of laser treatment at baseline were included. As in the main trial, there was a significant reduction in laser treatment for DR with fenofibrate versus placebo (from 4.6% to 1.0%, P = 0.0004). In patients with preexisting DR, the incidence of two-step ETDRS progression of retinopathy was significantly reduced in the fenofibrate group relative to placebo (from 14.6% to 3.1%, P = 0.004). This benefit was not seen in patients without DR. In addition, fewer patients developed "significant DR," a post hoc composite of DME, two-step progression of retinopathy or laser treatment of either eye, with fenofibrate compared with the placebo. The main drawback of this study was that retinal photographs were only collected in a 10% subsample. Secondly, the criteria followed by the participating centers to undertake laser treatment were not defined at entry and therefore are presumably heterogeneous, although the investigators were completely masked as to the allocation of fenofibrate treatment. However, these substantial benefits from reducing the need for laser would probably make us consider fenofibrates for our diabetic patients.
The ACCORD trial was also primarily a cardiovascular outcomes study, testing whether intensifying and extending current treatment approaches beyond those already recommended by guidelines (i.e., intensive vs. standard control of blood glucose or blood pressure, or adding fenofibrate against a background of simvastatin treatment) could have the benefit. It was a randomized trial conducted at 77 clinical sites in the United States and Canada. Combination treatment with fenofibrate plus simvastatin did not significantly impact cardiovascular outcomes in ACCORD Lipid. 
DR outcomes were evaluated in the 4-year ACCORD-eye sub-study. The 5518 participants with dyslipidemia were randomly assigned, to receive simvastatin in combination with either fenofibrate or a matching placebo. The primary outcome of the ACCORD-eye study was the composite end point of either progression of DR by at least three steps on the ETDRS severity scale or development of PDR necessitating photocoagulation therapy or vitrectomy. Intensive combination treatment for dyslipidemia (fenofibrate plus simvastatin) reduced the rate of progression of DR.  In contrast to FIELD, patients in this study had a longer duration of diabetes (mean 10.0 years vs. median 5.1 years) and a higher prevalence of preexisting DR (50% vs. 8%) at baseline. , However, the overall results of the ACCORD-eye study were consistent with those observed in the FIELD study. Treatment with fenofibrate (n = 806) was associated with a 40% decrease in retinopathy progression, defined as three or more steps on the ETDRS scale or PDR that needed either laser or vitrectomy treatment (from 10.2% to 6.5%, P = 0.006). There was no effect on the rate of moderate vision loss.  As for the FIELD study, the benefit was greater in patients with evidence of retinopathy at baseline. 
Safety concerns with fenofibrate include the possibility of myopathy in combination with a statin (although this was not observed in either the FIELD or the ACCORD Lipid studies), , increases in serum transaminases, reversible increases in serum creatinine and an increased risk for gallstones. These may be especially relevant in the older patient with multiple co-morbidities. Caution is also indicated when fenofibrate is used in patients receiving oral coumarin anticoagulants.
The two major fibrate randomized control trials (FIELD and ACCORD - lipid); demonstrated significant benefit on micro-vascular (i.e., retinopathy and nephropathy) outcome, possibly independent of lipid levels. It also showed a consistent effect of fenofibrate on DR progression, with a relative reduction of 30-40% over 4-5 years. In both studies, patients with pre-existing DR derived greater benefit. The number needed to treat (NNT) to prevent first laser treatment in the main FIELD study was 17 and to prevent DR progression was 9 in the FIELD ophthalmology substudy and 14 in ACCORD-eye. ,
Mechanism of Action of Fenofibrates
The FIELD and the ACCORD-eye studies have definitely shown a clear benefit with fenofibrate in preventing or arresting DR. However, the mode of action has not been well-understood. There are various proposed mechanisms for the same. Defining the mechanisms by which fenofibrate acts is important as this knowledge could allow physicians to better understand how to incorporate the drug in the management of patients with diabetes. 
Lipid Related Mechanisms
Fenofibrate has long been labeled a "lipid modifying drug" and is approved for the treatment of hypertriglyceridemia and mixed dyslipidemia. In addition to its main action in lowering plasma triglyceride levels, fenofibrate also lowers total and LDL cholesterol, raises apolipoprotein A-I (apo A-I) and high-density lipoprotein cholesterol and reduces the concentration of small LDL cholesterol particles and apo B. 
However, in both the FIELD and ACCORD-eye studies, no relationship was found between the lipid lowering effects of fenofibrate and the appearance or progression of DR. , The beneficial effects of fenofibrate in DR are probably not related to the serum lipid levels. Fenofibrate up-regulates apo A-I production in the liver  and there are recent data showing that the level of circulating apo A-I is an independent protective factor for DR development. , Studies have shown that apo A-I is overexpressed in the retina of diabetic patients. , Apo A-I is involved in the intraretinal reverse transport of lipids, thereby preventing lipid deposition and lipotoxicity, and is also a potent scavenger of reactive oxygen species. Apo A-I could therefore play an important role in protecting the retina from oxidative stress. Fenofibric acid (FA) has been shown to enhance expression of the gene for apo A-I in the liver,  as well as in macrophages and fibroblasts. 
Non-Lipid Related Mechanisms
There are also mechanisms independent of changes in lipids, which could account for the effects of fenofibrate or its active metabolite, FA, on DR.
Fenofibrates prevent the apoptosis of human retinal endothelial cells induced by serum deprivation through a PPARα-independent, but adenosine monophosphate-activated protein kinase (AMPK)-activated-dependent pathway. 
Antioxidant and anti-inflammatory activity
Fenofibrates may mitigate the adverse effects of oxidative and inflammatory stress implicated, together with other risk factors, in the development of micro-vascular dysfunction and retinopathy.  It prevents leucostasis, which is essential in the pathogenesis of PDR. FA also prevents retinal pigment epithelium (RPE) disruption induced by interleukin-1 β by suppressing AMPK activation, thus supporting the concept that inflammation and in particular interleukin-1 β, plays a crucial role in the pathogenesis of DME. 
Protective effects on blood-retinal barrier breakdown
Fenofibrates prevent the disorganization of tight junction proteins and hyperpermeability provoked by the diabetic milieu, as shown in cultures of human RPE cells which constitute the external blood-retinal barrier.  This should decrease DME. 
Experimental studies have demonstrated that PPARα activation has a neuroprotective effect.  This could be relevant in preventing neuroretinal degeneration, an early and crucial event that occurs in DR even before vascular abnormalities can be detected. 
Fenofibrates inhibit angiogenesis in vitro and in vivo as well as basic fibroblast growth factor induced angiogenesis in vivo. However, there are no convincing data on the anti-angiogenic action of FA in retinal endothelial cells or in any experimental model of DR.
Conclusions and Future Research
There remains a need for strategies that are effective in preventing DR or slowing down its progression, which are safe, well-tolerated and more effective, have a lower risk profile, easy to perform, have more predictable results with less morbidity than the current regimens. Physicians caring for diabetic patients not only need to maximize glycemic control, but also closely monitor and treat other systemic conditions. The consistency of clinical data from the FIELD and ACCORD-Eye studies is probably adequate to recommend the use of fenofibrate in early stages of DR.
Can we combine the effectiveness of the current standard procedures with the prevention and slowing down of progression of DR that fenofibrates can offer? Fenofibrates are probably a starting point, a new platform, an advance in the management of DR and probably a step forward. We need many more advances such as these.
Cost to the hospital and the patient is also a key consideration when considering the adoption of any new treatment. It could be postulated that the cost of fenofibrate is relatively low considering the NNT for preventing first laser treatment for DR progression. However, a specific pharmacoeconomic study on this issue is needed. Clear practice guidelines are required that promote evidence based management and also patient education.
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs are being used in the eye for many years now, but not much attention is being paid toward the safety of these drugs. This is of clinical relevance given that patients may require serial treatment over many years. Emerging data emphasize the need for heightened surveillance for systemic adverse events with intraocular anti-VEGF injections especially in the elderly primarily because they are already at increased risk of cardiovascular and cerebrovascular diseases. A standardized work-up protocol for all patients to receive these medications should be devised to monitor these adverse events. 
There remain several issues that are not addressed and are important areas for future research. Whom should fenofibrate be given to and for how long? The strongest evidence is for T2DM patients with early stages of DR,  but how about other diabetics? Questions remain regarding the specific mechanisms of this effect of fenofibrate. Knowledge of the primary mode of action of fenofibrate will be useful for both physicians and patients in determining how best to use this drug as an adjunct in the management of DR and ultimately facilitating the translation of clinical trial data to clinical practice.
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