13th June 2022, Dr Chee L Khoo
Fenofibrate is a commonly-used lipid lowering agent. In particular, it is recommended for patients with high triglycerides. Two previous studies have demonstrated that fenofibrate reduces the progression of diabetic retinopathy (DR) in patients who already have DR. Despite the benefits of fenofibrate, we don’t see recommendations for its use featured prominently in guidelines. For example, the American Academy of Ophthalmologists does not comment on its use for DR. The American Diabetes Association (ADA) recommends a “collaborative” approach to fenofibrate use in DR (whatever that means). We also see that DR is not an indication for fenofibrate use under the PBS. Hence, there is some confusion on when to use fenofibrate and who to use it on. What is the evidence thus far?
The FIELD study (1)
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus (T2D). Eligible patients were randomly assigned to receive fenofibrate 200 mg/day or matching placebo. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (3·4% patients on fenofibrate vs 4·9% on placebo; hazard ratio [HR] 0·69, p=0·0002; absolute risk reduction 1·5%). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0·66, p=0·022).
Of note, the mechanism of this effect does not seem to be related to plasma concentrations of lipids. Further, the reduction was only seen in patients who had pre-existing retinopathy at baseline and was ot seen in those without DR at baseline.
The ACCORD study (2)
The original Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was a 2×2 factorial, multicentre, randomised clinical trial in people with T2D who had cardiovascular disease or cardiovascular risk factors. There were three intervention arms in the trial. In the glycaemia arm, intensive glucose lowering vs standard treatment aimed for HbA1c <6.0% vs 7.0-7.9%; in the BP arm, they aim for systolic BP of <120 vs <140 mmHg and in the dyslipidaemia arm they compared fenofibrate plus simvastatin vs placebo plus simvastatin.
The primary outcome measure for all 3 intervention arms was the first occurrence of a major CVD event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in each of those intervention arms. However, the primary outcome were not achieved in any of the intervention arms. In fact, the trial was terminated 17 months early when excess deaths were detected in the intensive glycaemic control group. Among patients T2D at high risk for death and stroke, a strategy of lowering HbA1c to a mean of 6.4% was associated with excess mortality.
The ACCORD Eye study is a sub-study of the ACCORD trial (3). The primary outcome of the ACCORD Eye Study was a composite of ≥3 steps of progression along the diabetic retinopathy severity scale for persons or treatment of diabetic retinopathy with photocoagulation or vitrectomy in either eye. The primary eye outcome in both the glycaemia and dyslipidaemia (simvastatin plus fenofibrate) arms were reduced but only in patients who had retinopathy at baseline. Further, in the much smaller subset of patients with moderate or worse DR at baseline, no significant benefit to fenofibrate use was seen.
The Taiwanese Eye Study (4)
Does fenofibrate reduce the incidence of new onset retinopathy. Not according to the FIELD and ACCORD-Eye studies. Both the FIELD and ACCORD Eye studies showed that fenofibrate reduce the progression of retinopathy but only in those who already had retinopathy. In a population-based cohort study in Taiwan, 32,253 T2D patients without previous retinopathy were divided into two groups based on whether they were exposed to fenofibrate or not. They showed that long-term and regular use of fenofibrate reduce the onset of new retinopathy by 43% over the study period of 6-8 years. It also reduced the need for laser therapy by 41% over the same period. In other words, fenofibrate in this study reduce new onset retinopathy as well reduce progression of existing retinopathy.
The benefit of fenofibrate in reducing the progression of retinopathy in patients with diabetes was further confirmed in a study only released in April 2022 in the Journal of the American Medical Association (JAMA) (5). In a cohort study of 5835 fenofibrate users and 144 417 non fenofibrate users, Meer E et al found that fenofibrate a decreased risk of proliferative diabetic retinopathy and vision-threatening diabetic retinopathy (a composite outcome of either proliferative diabetic retinopathy or diabetic macular oedema). The participants already had retinopathy at baseline.
In summary, there is increasing evidence confirming the benefits of fenofibrate in reducing the progression of retinopathy. There is some early evidence that fenofibrate may reduce new onset retinopathy as well but we await more evidence. We hope that we can prescribe fenofibrate under the PBS soon to reduce the progression of retinopathy.
References
- Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d’Emden MC, Crimet DC, O’Connell RL, Colman PG; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007 Nov 17;370(9600):1687-97. doi: 10.1016/S0140-6736(07)61607-9. Epub 2007 Nov 7. PMID: 17988728.
- The Action to Control Cardiovascular Risk in Diabetes Study Group*, Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008;358:2545-59.
- Chew EY, Davis MD, Danis RP, et al; Action to Control Cardiovascular Risk in Diabetes Eye Study Research Group. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology. 2014;121(12):2443-2451. doi:10.1016/j.ophtha.2014.07.019
- Lin YC, Chen YC, Horng JT, Chen JM. Association of Fenofibrate and Diabetic Retinopathy in Type 2 Diabetic Patients: A Population-Based Retrospective Cohort Study in Taiwan. Medicina (Kaunas). 2020 Jul 31;56(8):385. doi: 10.3390/medicina56080385.
- Meer E, Bavinger JC, Yu Y, VanderBeek BL. Association of Fenofibrate Use and the Risk of Progression to Vision-Threatening Diabetic Retinopathy. JAMA Ophthalmol. 2022;140(5):529–532. doi:10.1001/jamaophthalmol.2022.0633