Purpose
To review clinical and experimental data for fenofibrate as a possible systemic treatment for diabetic retinopathy.
Design
Perspective.
Methods
Review of clinical studies focused on 2 major randomized controlled trials: the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes)-Eye studies. Progression was defined in FIELD as laser treatment for proliferative retinopathy or macular edema or increase by ≥2 steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and in ACCORD-Eye as ≥3 steps (ETDRS scale) or proliferative disease requiring laser or vitrectomy treatment. Experimental studies investigating the mode of action of fenofibrate were reviewed.
Results
The 2 trials included 11 388 patients with type 2 diabetes mellitus, of whom 5701 were treated with fenofibrate (± statin) for up to 5 years. Fenofibrate reduced first laser treatment by 31% ( P = .0002), and progression of diabetic retinopathy with absolute reductions of 5.0% over 5 years ( P = .022, FIELD) and 3.7% over 4 years ( P = .006, ACCORD-Eye). There was greater benefit in patients with than without preexisting retinopathy. The putative mechanisms implicated in the mode of action of fenofibrate involve lipid and nonlipid pathways, including beneficial effects on apoptosis, oxidative stress, inflammation, blood-retinal barrier breakdown, and neuroprotection.
Conclusions
There are now robust and consistent clinical data to recommend fenofibrate as an adjunctive treatment for early diabetic retinopathy in patients with type 2 diabetes mellitus, taking into account the risks vs benefits of therapy. Further elucidating its mode of action will help to refine how best to use fenofibrate in the management of diabetic retinopathy.
Diabetic retinopathy (DR) is a worldwide public health problem. Based on current estimates, 366 million people have diabetes, predominantly type 2 diabetes mellitus (T2DM). Of these, about 1 in 3 have signs of DR and 1 in 10 have vision-threatening complications, including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).
In the United States alone, annual direct medical costs for management of DR are already estimated at $492 million, and indirect costs attributable to loss of patient quality of life and reduced work productivity are likely to be substantially higher. DR typically evolves asymptomatically until visual loss develops, over an average of 15 years. Even if many people with diabetes may not develop vision-threatening stages of DR in the short term, it is likely that increases in the number and longevity of people with diabetes will substantially impact the public health burden of DR over time.
While there have been effective treatments for vision-threatening retinopathy, these have well-recognized limitations. Over the past 4 decades, laser photocoagulation has been the mainstay of therapy for DME and PDR in preventing moderate or severe visual loss, respectively. Laser treatment, however, is inherently destructive and requires equipment and skilled ophthalmologists, often not widely available in many developing countries. Improvements in vitreoretinal surgical techniques have also allowed more advanced stages of DR, such as severe vitreous hemorrhage and secondary retinal detachment, to be effectively managed. New therapies such as intraocular injection of steroids and anti–vascular endothelial growth factor (VEGF) agents may have application in patients with DME who respond poorly to conventional laser therapy. In fact, anti-VEGF agents have now been suggested as primary treatment for DME and appear superior to laser treatment alone. However, these new therapies are costly and invasive, and pose a risk of local and systemic adverse effects. Clearly, there is a need to direct research and strategic efforts to preventing DR.
The cornerstone for prevention is effective screening and optimal control of risk factors, principally glycemia and blood pressure. In 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 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 multifactorial intervention persisted after a further 5 years, it is worth noting that about one-half of 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 1c <6.5%) offers additional benefit compared with standard care, the lack of cardiovascular benefits and increased mortality associated with this approach questions its suitability. 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 United Kingdom Prospective Diabetes Study. Finally, treatment approaches specifically targeting dyslipidemia (eg, statins) have not shown any significant benefits for DR.
What other possibilities are available to help to address the burden of DR? Early angiotensin receptor blockade appears to be of benefit in patients with type 1 diabetes mellitus (T1DM). In the Renin–Angiotensin System Study (RASS), treatment with either enalapril or losartan reduced DR progression by 65% ( P = .02) and 70% ( P = .008), respectively. Additionally, in the DIRECT (Diabetic REtinopathy Candesartan Trials) program, candesartan reduced the incidence of DR in patients with T1DM (by 26%, P = .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.
Fenofibrate and Diabetic Retinopathy: Clinical Data
In the last 5 years, 2 major prospective randomized controlled trials have indicated potential for fenofibrate, a peroxisome proliferator activated–receptor alpha (PPARα) agonist, in preventing or arresting the progression of DR in patients with T2DM. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and ACCORD-Eye, a substudy of the National Institutes of Health–funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, showed consistent beneficial effects with fenofibrate in slowing the progression of DR. In total, 11 388 patients with T2DM were included, of whom 5701 were treated with fenofibrate (± statin) for up to 5 years.
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. At 5 years, fenofibrate did not significantly reduce the primary study outcome, a composite of coronary heart disease death and myocardial infarction (11% relative risk reduction [RRR] vs placebo, P = .16), although the overall incidence of cardiovascular events was reduced significantly (11% RRR, P = .035). One of the prespecified tertiary endpoints of the study was need for laser photocoagulation. Among 814 patients (8%) with DR at baseline, 3.6% of patients treated with fenofibrate vs 5.2% in the placebo group required laser therapy over 5 years ( P = .0003).
These data were subsequently adjudicated and analyzed by reading center staff and an ophthalmologist, masked to treatment allocation. Consistent with the original findings, fenofibrate treatment was associated with a significantly reduced need for first or repeated laser treatment for retinopathy, with greater absolute benefit observed for patients with rather than without retinopathy at baseline ( Table 1 ). Nevertheless, 2 caveats should be made. First, retinal photographs were only collected in a 10% subsample. Given that the initial status of the retina is the main determinant of requirement for laser therapy during follow-up, knowledge of the status of the retina at study entry is a key piece of information. Second, 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.
| Parameter | Placebo | Fenofibrate | P | NNT b |
|---|---|---|---|---|
| Main FIELD study | ||||
| Total no. of patients | 4900 | 4895 | ||
| First laser treatment for DR | 4.9 | 3.4 | .0002 | 66 |
| – No retinopathy history | 2.8 | 1.7 | .0008 | 90 |
| – Prior retinopathy | 27.4 | 21.6 | .06 c | 17 |
| Any laser treatment for DR, n | 535 | 337 | .0003 | — |
| – No retinopathy history | 257 | 131 | .0002 | — |
| – Prior retinopathy | 278 | 206 | .01 d | — |
| FIELD ophthalmology substudy | ||||
| Total no. of patients | 500 | 512 | ||
| Laser treatment for DR | 4.6 | 1.0 | .0004 | 27 |
| 2-step progression of retinopathy (ETDRS scale) | ||||
| – All patients | 12.3 | 9.6 | .19 | 37 |
| – No retinopathy history | 11.7 | 11.4 | .87 | 333 |
| – Prior retinopathy | 14.6 | 3.1 | .004 e | 9 |
| Composite outcome f | 16.1 | 11.1 | .022 | 20 |
a Data are given as absolute event rates (%) except where indicated.
b NNT = 1/absolute risk reduction.
c P value for interaction for prior/no prior retinopathy history: .30.
d P value for interaction for prior/no prior retinopathy history: .10.
e P value for interaction for prior/no prior retinopathy history: .019.
f Post hoc composite outcome defined as 2-step progression of Early Treatment Diabetic Retinopathy Study retinopathy grade, macular edema, or laser treatment.
The FIELD study also incorporated an ophthalmology substudy in which standardized fundus photographs were routinely taken. In this substudy, 1012 patients without evidence of clinically significant retinopathy (proliferative or severe nonproliferative disease), DME, or history of laser treatment at baseline were included. As in the main trial, there was significant reduction in laser treatment for DR with fenofibrate vs placebo (from 4.6% to 1.0%, P = .0004). In patients with preexisting DR, the incidence of 2-step Early Treatment Diabetic Retinopathy Study (ETDRS) progression of retinopathy, the primary endpoint in the substudy, was significantly reduced in the fenofibrate group relative to placebo (from 14.6% to 3.1%, P = .004), although not in patients without DR. Additionally, fewer patients developed “significant DR,” a post hoc composite of DME, 2-step progression of retinopathy, or laser treatment of either eye, with fenofibrate compared with placebo ( Table 1 ).The main caveat to these findings in the substudy was the small numbers of patients with these events over the 6-year follow-up period.
The ACCORD trial was also primarily a cardiovascular outcomes study, testing whether intensifying and extending current treatment approaches beyond those already recommended by guidelines (ie, intensive vs standard control of blood glucose or blood pressure, or adding fenofibrate against a background of simvastatin treatment) could have benefit. 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 substudy. 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 3 or more steps on the ETDRS scale or PDR that needed either laser or vitrectomy treatment (from 10.2% to 6.5%, P = .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 ( Table 2 ). In both studies, fenofibrate did not impact deterioration in visual acuity.
| Parameter | Placebo (N = 787) | Fenofibrate (N = 806) | P | NNT c |
|---|---|---|---|---|
| Progression of DR b | ||||
| All patients | 10.2 | 6.5 | .006 | 27 |
| – No retinopathy history | 6.4 | 6.2 | .03 d | 500 |
| – Prior retinopathy | 13.6 | 6.7 | .03 d | 14 |
a Data are given as absolute event rates (%).
b Defined as 3-step progression of Early Treatment Diabetic Retinopathy Study retinopathy grade or development of diabetic retinopathy requiring laser photocoagulation or vitrectomy.
c NNT = 1/absolute risk reduction.
d P value for interaction for some retinopathy/no retinopathy at baseline P = .03.
Potential safety concerns identified in these trials include reversible increases in plasma homocysteine and creatinine (by ∼41% and 15%, respectively, at 1 year in FIELD). However, subsequent analyses of the FIELD study showed no increased risk of deterioration in renal function with fenofibrate. Fibrates have also been associated with muscle toxicity, an effect that is more pronounced in patients also treated with a statin. Glucuronidation, which is an important pathway for renal excretion of lipophilic statins, appears to be significantly inhibited by gemfibrozil but not fenofibrate. In this regard, it has been reported that simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate. In the ACCORD study there was no evidence of any increase in myopathy or significant elevations of creatine kinase and alanine aminotransferase in patients receiving fenofibrate plus simvastatin in comparison with those treated with simvastatin alone.
In summary, 2 major clinical trials demonstrated a consistent effect for fenofibrate on DR progression, with a relative reduction of 30% to 40% over 4 to 5 years. In both studies, patients with preexisting 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. In comparison, the anti-VEGF drug ranibizumab, in addition to laser treatment, was associated with a NNT of 25 to prevent 2-step ETDRS progression in patients with DME. Studies evaluating the role of anti-VEGF therapy in PDR have not been conducted in sufficient patient numbers to permit meaningful comparison. However, the clinical context between the 2 therapies is different; anti-VEGF therapy is currently used for treatment of later and more severe stages of DR while fenofibrate is used for earlier stages of DR. Additionally, as previously discussed, there is a risk of potentially serious complications associated with use of anti-VEGF therapy, which is of clinical relevance given that patients may require serial treatment over many years.
Taking these data into consideration, we believe that the FIELD and ACCORD-Eye data provide strong justification for the use of fenofibrate to prevent DR progression in patients with preexisting disease.
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