Dr Paul Chous
MA OD FAAO
Specialising in Diabetes Eye Care and Education
Tacoma WA, USA
Diabetic retinopathy (DR) remains the leading cause of severe vision loss in working-age people in the industrialised world. Tight blood glucose and blood pressure control are the mainstays of delaying the onset and preventing the progression of diabetic retinopathy to a stage that requires laser or anti-VEGF intervention. Nonetheless, it is estimated that 10 per cent of people living with diabetes have sight-threatening diabetic retinopathy (STR), proliferative diabetic retinopathy (PDR) and/or diabetic macular oedema (DME).1
Validated risk analysis shows that among newly-diagnosed diabetes patients with excellent metabolic control (glycosylated haemoglobin of 6.5 per cent and blood pressure of 120/80), four per cent will develop STR within 10 years.2 With the appearance of even mild non-proliferative diabetic retinopathy (NPDR), the 10-year risk jumps to eight per cent. The risk for most patients is substantially higher, given the fact that more than 50 per cent have an HbA1c greater than seven per cent.3 Though photocoagulation and intra-vitreal injections reduce the risk of significant vision loss from STR substantially, they don’t eliminate that risk, may cause loss of visual function and require considerable expenditure.
Is there anything more we can do to prevent our patients from progressing to sight-threatening diabetic retinopathy?
Two large clinical trials examining more than 11,000 type 2 diabetes patients have recently demonstrated that use of the oral lipid agent, fenofibrate significantly reduced the risk of DR progression and need for first laser treatment. The FIELD study (Fenofibrate Intervention and Event Lowering in Diabetes) conducted in Australia showed that patients with mild to moderate NPDR and non-clinically significant DME treated with 200 mg fenofibrate over five years were 78 per cent less likely to have significant (two-step Early Treatment Diabetic Retinopathy Study) progression of retinopathy, had a 31 per cent lower risk of laser for Clinically Significant Macular Edema (CSME), and a 30 per cent lower risk of laser for PDR over five years (37 per cent overall reduced risk of laser for both conditions).4 The effect was much smaller and non-significant for patients without pre-existing retinopathy. Though only one in five patients had retinal photography to document DR severity, the benefits appear robust.
In addition, a sub-study of the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) conducted in North America, ACCORD-Eye also showed that type 2 patients with high cardiovascular risk and mild-to-moderate retinopathy placed on 160 mg fenofibrate (+/- statin therapy) were 40 per cent less likely to have either a three-step ETDRS progression of retinopathy (documented by serial retinal imaging) and/or laser treatment for PDR over four years.5
Subjects in ACCORD-Eye had longer diabetes duration and higher prevalence of any DR than subjects in FIELD at baseline and, again, these positive effects were present but much weaker in patients without pre-existing retinopathy. Of significance, only 17 patients need to be treated with fenofibrate to prevent one case of initial laser therapy (per FIELD) and 9/14 patients to prevent significant progression of NPDR (FIELD and ACCORD-Eye, respectively), NNTs that are much lower than those for commonly used therapies such as statins and antihypertensives.
The benefits of fenofibrate for DR in these studies appear to be largely independent of both the drug’s lipid-lowering effects6 and patients’ glycosylated haemoglobin levels. Proposed mechanisms include inhibition of retinal capillary apoptosis (via AMPK-dependent pathways),7 retinal oxidative stress (via suppression of nfK),8 and leukocyte adhesion to capillary endothelium (via suppression of intracellular adhesion molecule-1); neuro-protection afforded by peroxisome proliferator-activated receptor-alpha (PPAR-);9 strengthening of capillary tight junctions;10 PPAR-mediated suppression of VEGF and hypoxia inducible factor-1.11
Unfortunately, there are no reported data from either FIELD or ACCORD-Eye for treatment efficacy among patients with varying degrees of NPDR or specific retinopathic findings. Subjects with severe NPDR, PDR, and CSME were excluded from both trials. Further investigations of benefit in DME and patients with type 1 diabetes are underway in Australia and the US (FAME-1 Eye).
Which patients with diabetes and DR merit consideration for adjunctive treatment with fenofibrate?
Australia’s Therapeutic Goods Administration recently approved fenofibrate (Lipidil, Abbott Pharmaceuticals) to slow the progression of existing DR in patients with type 2 diabetes, and some ophthalmologists and optometrists are beginning to recommend patients discuss the risks and benefits of fenofibrate with their primary care physicians, internists and endocrinologists. Pharmacology experts with whom I have consulted tell me fenofibrate is generally safe and well-tolerated (Table 1).
Table 1. Contraindications to fenofibrate therapy12
The recommended dosage is one tablet (144 mg) daily, or one to two (48 mg) tablets in patients with renal insufficiency, depending on creatinine clearance values. Common side-effects include gastrointestinal upset. Several drug interactions are reported, including increased risk of muscle pain/weakness (low risk almost exclusively in patients also on statin therapy),13 bleeding in patients taking anticoagulants (close monitoring of serum coagulation laboratory markers—primarily prothrombin time (PT) in patients on warfarin—recommended), and use with other drugs potentially impairing liver/renal function. Hypoglycaemia is rare (less than one per cent of patients) but all patients on insulin or sulfonylureas should be cautioned to closely monitor their glucoses when initiating therapy. Though recent analysis of glucagon-like Peptide-1 (GLP-1) diabetes drugs like exenatide (Byetta, Lilly) and liraglutide (Victoza, NovoNordisk) has shown no increased risk of pancreatitis,14 patients simultaneously using these agents with fenofibrate should be specifically informed about symptoms of acute pancreatitis like acute abdominal pain, nausea and fever.
I have encountered differing opinions about add-on fenofibrate among retinal specialists in the USA and Australia, with several indicating they do or would use fenofibrate mainly in the context of DME requiring laser intervention (interestingly, an application for which there is no randomised controlled trial evidence), whereas others see merit in earlier intervention, especially for patients with reduced vision in one eye. My thoughts about which patients deserve consideration are informed by my review of the available evidence and a commitment to earlier intervention and prevention in patients with significant risk of vision loss, and are summarised in Table 2.
Table 2. Diabetes patients who should be considered for adjunct preventive therapy against DR with fenofibrate
Independently of the strong evidence favouring fenofibrate against DR progression, there is emerging evidence that other novel strategies may prove useful, including blockade of the rennin-angiotensin system with ACE inhibitors and angiotensin receptor blocking (ARB) drugs15 and micronutrient intervention with molecules like benfotiamine, Pycnogenol and zeaxanthin that block intermediate biochemical pathways linking hyperglycaemia to DR.
I am currently conducting a small clinical trial—the Diabetes Visual Function Supplement Study (DiVFuSS - ClinicalTrials.gov Identifier: NCT01646047)—evaluating visual function in diabetes patients with a combination of these molecules. This combination has been shown to normalise retinal structure, metabolism and function in an animal model of the disease.16
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3. Gitt AK, Schmieder RE, Duetting E, Bramlage P, Schneider S, Tschöpe D; DIALOGUE Study Group. Achievement of recommended glucose and blood pressure targets in patients with type 2 diabetes and hypertension in clinical practice - study rationale and protocol of DIALOGUE. Cardiovasc Diabetol 2012; 11: 148.
4. Keech AC, Mitchell P, Summanen PA et al. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370: 9600: 1687-1697.
5. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363: 3: 233-244.
6. ACCORD Study Group; ACCORD Eye Study Group. Chew EY, Ambrosius WT, Davis MD, Danis RP et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363: 233-244.
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10. Trudeau K, Roy S, Guo W, Hernández C, Villarroel M, Simó R et al. Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: Functional implications in retinal permeability. Invest Ophthalmol Vis Sci 2011; 52: 6348-6354.
11. Meissner M, Stein M, Urbich C et al. PPARalpha activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation. Circ Res 2004; 94: 324-332.
12. Accessed at http://www.drugs.com/pro/Fenofibrate.html, March 29, 2014.
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14. Egan AG, Blind E, Dunder K et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med 2014; 370: 794-797.
15. Sjølie AK, Dodson P, Hobbs FR. Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review. Int J Clin Pract 2011; 65: 2: 148-153.
16. Kowluru RA, Zhong Q, Santos JM, Thandampallayam M, Putt D, Gierhart DL. Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. Nutr Metab (Lond) 2014; 11: 1: 8.