Effect of Fenofibrate on Progression of Diabetic Retinopathy

Abstract

Background: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy.

Methods: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy.

Results: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m² lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo.

Conclusions: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).

Figure 1. Referable diabetic retinopathy or maculopathy, or treatment for diabetic retinopathy or maculopathy

Shown are the results of the primary composite outcome of referable diabetic retinopathy or maculopathy, or treatment thereof, with intra-vitreal injection of medication, retinal laser therapy or vitrectomy. The primary outcome occurred in 131 participants (22.7%) in the fenofibrate group and in 168 participants (29.2%) in the placebo group, representing 65 fewer primary outcome events per 1000 participants in the fenofibrate group than in the placebo group over a median of 4.0 years of follow-up.

Figure 2. Primary and secondary eye outcomes

The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy, or treatment thereof, with intra-vitreal injection of medication, retinal laser therapy or vitrectomy. Secondary retinopathy outcomes were any progression of diabetic retinopathy or maculopathy; development of exudates or blot hemorrhages within one disc diameter of the macula; development of macular edema; and components of the primary outcome (namely referable diabetic retinopathy or maculopathy; and treatment for diabetic retinopathy or maculopathy). A single participant may have had multiple events and therefore may contribute information to more than one row. The area of each box is proportional to the inverse of the variance of the log hazard ratios. The diamond represents the result of the primary analysis, with the width of the diamond indicating the 95% confidence interval. The dashed vertical line indicates the hazard ratio for the primary outcome in the overall population. Confidence intervals for the secondary eye outcomes have not been adjusted for multiplicity, and should not be used to infer clinical utility. These results exclude adverse events not related to diabetic retinopathy or maculopathy, namely: macular edema (2 participants) and treatment with laser, intravitreal injection or vitrectomy (6 participants) in the fenofibrate arm, and macular edema (3 participants) and treatment (4 participants) in the placebo arm due to macular degeneration or retinal vein occlusion or a dropped lens.

Figure 3. Primary outcome in pre-specified subgroups

Shown are the hazard ratios for the primary outcome in prespecified subgroups defined according to baseline characteristics. The area of each box is proportional to the inverse of the variance of the log hazard ratios. The arrow indicates that the boundary of the 95% confidence interval is outside the graphed area. The diamond represents the result of the primary analysis, with the width of the diamond indicating the 95% confidence interval. The dashed line indicates the hazard ratio in the overall population.