Fenofibrate staves off vision loss in diabetes

The antilipidemic drug fenofibrate averts or delays diabetic retinopathy (DR) in diabetes patients with early retinal changes in the LENS trial, potentially paving the way for the least invasive route of drug delivery in this population.

Over 4 years, fenofibrate reduced the progression of diabetic retinopathy or maculopathy by 27 percent vs placebo (hazard ratio [HR], 0.73; p=0.006) in this trial of more than 1,100 patients with diabetes. [NEJM Evid 2024;3(8):EVIDoa2400179]

The benefits were seen in patients with either type 1 or 2 diabetes and those with normal or impaired kidney function.

“The trial addresses a common cause of permanent visual loss for which there are limited therapeutic options,” said lead author Dr David Preiss from the University of Oxford in the UK at ADA 2024. “We’ll be interested to see the uptake in routine care with the repurposing of an old drug. We’re trying to prevent people from having a retinal laser or an intravitreal injection as those treatments have significant downsides.”

Potential complications of these common interventions include transient pain and discomfort, corneal abrasion, and iritis.

Putting data in context: new supports the old

Previous trials of fenofibrate showed a reduced need for laser treatment in patients and some beneficial effects on the progression to diabetic retinopathy, which is an important microvascular complication of diabetes. [Lancet 2007;370:1687-1689; N Engl J Med 2010;363:233-244]

“The result is encouraging and fits the previous findings,” said session moderator Professor Thomas Gardner from the University of Michigan in Ann Arbor, Michigan, US. “The trial suggests that retinopathy progression can be reduced by almost a third, which is substantial. This can be done with a safe and inexpensive drug that is taken by mouth.”

He emphasized that controlling HbA_1c is not the whole story. “When patients have microaneurysm or small haemorrhage, for which there is no ocular treatment, having a systemic therapy like fenofibrate would make a lot of sense.”

Fenofibrate outcomes

Preiss and his team followed adults with diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) programme in Scotland. From September 2018 through July 2021, the 16-centre LENS trial was embedded into routine clinical care at 11 National Health Service centres in Scotland.

A total of 1,151 patients with mild retinopathy or maculopathy were randomly assigned to receive fenofibrate 145 mg or placebo daily (or every other day in those with impaired kidney function).

The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy or treatment for both (intravitreal injection, retinal laser or vitrectomy).

Complete data were available for 1,149 individuals. Of these, 27 percent had T1D, and 23 percent had an eGFR* <60 mL/min/1.73 m².

The primary outcome of time to the first occurrence of a composite of diabetic retinopathy or maculopathy (based on the DES grading scheme) or treatment for diabetic retinopathy or maculopathy (intravitreal injection, retinal laser therapy, or vitrectomy) in either eye occurred in 22.7 percent of patients treated with fenofibrate vs 29.2 percent with placebo.

Progression of retinopathy or maculopathy was also significantly less common with fenofibrate than placebo (32.1 percent vs 40.2 percent), as was referral for treatment (18.6 percent vs 25.9, respectively). Macular oedema occurred in 3.8 percent of patients on fenofibrate vs 7.5 percent in the placebo group.

“There were no significant differences between the two groups in visual function, quality of life, or visual acuity, which was unsurprising as these individuals had early retinopathy without visual impairment,” Preiss explained.

Major cardiovascular events or nontraumatic lower limb amputations were comparable between groups. There was no impact on urine albumin/creatinine ratio whereas total and non-HDL cholesterol levels were slightly lower and triglyceride significantly 13.7 percent lower with fenofibrate.

Renal harm paradox

Interestingly, the eGFR was 7.9 mL/min/1.73 m² lower in the fenofibrate group throughout the study. “Although there was a significant difference, this effect was reversible,” said Preiss.

“We’ve known that fenofibrate increases blood creatinine levels by about 15 percent, and this increase is reversible. If you stop the drug four weeks later, your renal function is back to where it was before.”

“Seeing the renal function, those not used to the drug may incorrectly assume that it is [causing] renal harm when it’s not,” added Preiss. “It's entirely reversible and may even be renoprotective, although it requires monitoring for creatinine elevation and some subtlety in clinical management.”

Moving on, his team will assess eye and kidney function in LENS participants in the next 10 years.

Gardner noted that ophthalmologists may take time to embrace a systemic treatment for early retinopathy, given the regulatory hurdles. “But if I were seeing an individual with mild retinopathy now, I would certainly discuss fenofibrate. If we really wanted to shift the dial, we need to decide what to do with these people with early disease who aren't seeing a specialist.”