Retinopathy and fenofibrate; results coming soon

[Eddy Edson]

Fenofibrate is a (more or less) failed lipid lowering medication but secondary outcomes from large scale trials over quite a few years have demonstrated a modest improvement in diabetic retinopathy progression. There's some mechanism apparently unrelated to lipids which delivers microvascular benefits.

Here in Oz, it's an approved treatment diabetic for retinopathy - I take it. This *may* (sarcasm) have something to do with the fact that the lead investigator on one of the trials was a well-connected Australian guy. Just about everywhere else, the lack of studies with retinopathy progression as a primary endpoint explains the lack of adoption (also I think the lack of a well-defined mechanism).

This may now change, with the first large-scale primary retinopathy trial for fenofibrate scheduled to report results in a few hours at the annual ADA conference: https://www.ctsu.ox.ac.uk/lens

THE LENS TRIAL​

Fenofibrate is a well-known cholesterol-lowering medicine that has been used for more than 20 years. Two major trials conducted in patients with diabetes suggested that taking fenofibrate may slow down the progression of retinopathy by 30% to 40%. However, conclusive information is needed.

The LENS (Lowering Events in Non-proliferative retinopathy in Scotland) trial tested whether taking fenofibrate tablets on a regular basis for about four years would slow the progression of retinopathy compared to placebo.

LENS recruited over a thousand participants with diabetes and observable retinopathy from across mainland Scotland.

LENS is coordinated by the University of Oxford and was run in close partnership with the Universities of Glasgow, Aberdeen, Dundee and Edinburgh, and with NHS Scotland’s Diabetic Eye Screening Service. The University of Oxford sponsors the trial which was funded by the National Institute of Health and Care Research.

Will be really interesting to see these results. The secondary outcomes from the various trials to date have generally shown real if modest benefits. Will this trial report strong enough data to support widespread adoption of fenofibrate treatment?

Another fenofibrate/retinopathy trial, FAME 1 EYE, this one for T1D's, will be reporting on its progress in the same session - but not final results. https://ctc.usyd.edu.au/our-research/research-areas/diabetes/active-trials/fame-1-eye-trial/

(Another secondary benefit seen in one of the early trials was a big reduction in diabetic foot amputations. Again, a microvascular effect with an unclear mechanism. This is actually a bit more interesting for me. I don't have any signs of retinopathy progression but I do have microvascular damage in my ankle and lower calf as part of my peripheral artery disease. I found a big, fast improvement when I started taking fenofibrate a couple of years ago - daily steps quickly went up by 2,000+. Maybe just post hoc without being propter hoc, I guess. Anyway, I've never seen any signs of research interest or follow-up for this indication for the drug).

 

[Eddy Edson]

Bottom line: 27% reduction in the risk of retinopathy progression. Also, reduced risk of macular oedema and maculopathy.

DUK story: https://www.diabetes.org.uk/about-u...l-lowering-drug-slows-progression-retinopathy

New results from a major trial show an existing drug that’s usually used to lower cholesterol can slow eye damage in people with diabetes.
People treated with a drug fenofibrate at the first signs of eye damage were less likely to need specialist care or treatment for diabetic retinopathy compared to people who took a placebo tablet.
These results from the LENS (Lowering Events in Non-proliferative retinopathy in Scotland) trial were announced at the American Diabetes Association Scientific Sessions.
Retinopathy happens when high blood sugar levels over time cause damage to blood vessels at the back of the eye. Current treatments only work in the later stages of damage, and don’t work well for everyone. So scientists are searching for ways to intervene sooner.
The LENS trial involved 1,151 adults with type 1 diabetes or type 2 diabetes who attended annual eye screening in Scotland, and had early signs of retinopathy.
Half the volunteers took fenofibrate daily or every other day, and the other half were given a placebo. Fenobibrate is a tablet that has been used to treat people with high cholesterol for over 30 years.

The research findings​

Researchers at the University of Oxford who led the trial followed the volunteers over four years. They saw people treated with fenobibrate had a 27% reduced risk of needing referral for specialist care or treatment for retinopathy, compared to those who received the placebo.
They also found that treatment with fenofibrate was linked with a lower risk of developing macular oedema (swelling at the back of the eye).
The benefits of fenofibrate were similar in people with type 1 diabetes or type 2 diabetes, and in people with healthy kidney function or kidney problems.
Researchers think the treatment works directly within the eye, but they need more evidence to understand exactly how it helps to slow retinopathy.
Dr David Preiss from the University of Oxford led the study. He said:

“Diabetic retinopathy remains a leading cause of visual loss. Management of blood glucose is important but this is very difficult to achieve for many people, and there are few other treatments available.
“We need simple strategies that can be widely used to reduce the progression of diabetic eye disease. Fenofibrate may therefore provide a valuable addition to treat people with early to moderate diabetic retinopathy.”

Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said:

“Eye problems are a frightening and too frequent complication of diabetes. But acting early can stop the first signs of damage progressing into devastating sight loss.
“We’re excited by the positive results from this major trial of a new treatment to slow progression of eye damage, which has the potential to benefit many people with diabetes in the UK.”

These results are broadly consistent with the secondary outcomes from previous trials & presumably come as no suurprise. But this focused RCT will no doubt support the case for fenofibrate as a standard treatment for early diabetic retinopathy. Cost effectiveness should not be an issue (generic drug, relatively cheap and widely available) and the safety profile is well understood.

On the other hand, the effectiveness is fairly modest, in absolute terms. Eg: On the composite endpoint used for this trial, 29.2% of the placebo group had retinopathy progression over an average of 4 years, versus 22.7% for the the fenofibrate group.

 

[Eddy Edson]

This study has sparked some discussion of the old results suggesting reductions in diabetic foot ulcer amputations, mentioned above. Also reduction in CKD issues.

See eg:

https://twitter.com/x/status/1805004896590029163

The 2011 paper Dayspring references: https://pubmed.ncbi.nlm.nih.gov/21576195/

Microvascular complications are common in type 2 diabetes in primary care. Intensified management of glycaemia or blood pressure had little effect on microvascular complication rates in recent large trials (ADVANCE, VADT, ACCORD). In 2005, the FIELD study demonstrated a significant reduction in the need for laser treatment for retinopathy, and of progression of renal dysfunction, with fenofibrate versus placebo. The FIELD ophthalmology sub-study showed that fenofibrate reduced the risk of new retinopathy and progression of retinopathy. Also, fenofibrate versus placebo significantly reduced the risk of non-traumatic, diabetes-related amputations in a post-hoc analysis from FIELD. Recently, the results of the ACCORD Lipid study were consistent with these findings, as fenofibrate significantly reduced progression of retinopathy and albuminuria, apparently independent of effects on lipids. These findings suggest a role for fenofibrate in the prevention of major diabetic microvascular complications.

 

[Eddy Edson]

Two possible reasons for the slow/limited follow up to these old microvascular suggestive results:

- Nobody is going to make any money out of fenofibrate sales (went generic a long time ago) so no pharma sponsorship for large trials.

- Taint of failure: fibrates were supposed to be the next wonder drug for CVD, but they failed for this.