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Use of the cholesterol-lowering drug fenofibrate had a modest but statistically significant association with reduced risk of vision-threatening diabetic retinopathy (VTDR), according to results of a large multicenter cohort study.

For the composite endpoint of VTDR, a fully adjusted model showed that fenofibrate use was associated with an 8% lower risk of progression versus non-use (HR 0.92, 95% CI 0.87-0.98, P=0.01).

Fenofibrate use had a more pronounced impact on the risk of proliferative diabetic retinopathy, with a 24% decrease in progression (PDR; HR 0.76, 95% CI 0.64-0.90) but did not significantly affect the risk of developing diabetic macular edema (DME; HR 0.96, 95% CI 0.90-1.03, P=0.27).

The findings are consistent with evidence that fenofibrate may protect against diabetes-associated breakdown of the blood-retinal barrier, although ophthalmologists rarely use the medication to treat diabetic eye disease, reported Brian L. VanderBeek, MD, of the Scheie Eye Institute in Philadelphia, and coauthors, in .

"Our positive association for progression to PDR coincides with results of previous clinical trials and adds new information with regards to the impact on DME," the authors stated.

Protection against progression to PDR "was found without regards to underlying NPDR [nonproliferative diabetic retinopathy] severity level, which is not well coded within the claims database," the group continued. "Understanding this limitation and how the inclusion of NPDR severity levels that may not benefit from fenofibrates would bias our findings to the null means that the positive association seen in our study is actually an underestimate of the true association."

Despite an unclear understanding of fenofibrate's potential mechanism of action in diabetic retinopathy, "interest in the use of this oral agent has become substantial," noted the author of an .

"From the point of view of a clinician with a long-time interest in diabetic retinopathy, its causal mechanisms, and its evolving treatments, the possibility that an oral medication originally used for a different disease may be beneficial for the management of diabetic eye disease is exciting," wrote Robert N. Frank, MD, emeritus of Wayne State University's Kresge Eye Institute in Detroit.

"The evidence that fenofibrate can slow the progression of diabetic retinopathy is growing, but it has not yet become a widely accepted treatment," he added. "It will be interesting to see how this large population analysis and the results from the ongoing randomized clinical trial will affect clinical practice in the years to come."

Two clinical trials that evaluated fenofibrate's effect on diabetic eye disease yielded different findings. The showed an association between fenofibrate use and fewer laser treatments for DME and PDR but not necessarily overall diabetic retinopathy progression. The showed less progression in diabetic retinopathy severity but did not specifically address DME or PDR. Both trials suggested the benefits were limited to patients with mild nonproliferative eye disease.

In subsequent clinical statements, the did not comment on fenofibrate use, and the called for a collaborative approach to fenofibrate use in diabetic retinopathy, VanderBeek and co-authors noted.

In an effort to inform decision-making about fenofibrate use in diabetic eye disease, VanderBeek and colleagues queried a large health insurer database for adults who had laboratory values associated with NPDR from January 2002 through June 2019. They excluded patients who had a diagnosis of VTDR within 2 years of insurance coverage. The primary outcomes were a new diagnosis of VTDR (composite of PDR or DME) or DME and PDR individually.

The analysis comprised 150,252 patients, of whom 5,835 (3.9%) used fenofibrate. During follow-up, 27,325 patients progressed to VTDR, including 4,086 to PDR and 22,750 to DME. Men accounted for a larger proportion of fenofibrate users (61.1% vs 51.0% of nonusers). Otherwise, patients with and without fenofibrate use had similar baseline characteristics.

The authors acknowledged limitations of the study: inability to reference direct clinical findings, reliance on a single medical claims database, and disregard for duration of fenofibrate use.

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