Another Study Shows Fenofibrate Benefit on Diabetic Retinopathy

Becky McCall

September 23, 2022

STOCKHOLM, Sweden — Adding fenofibrate to a statin was associated with an 11% lower risk of diabetic retinopathy progression in patients with type 2 diabetes, new study data show. The drug combination was also found to reduce the risk of intravitreous injection therapy by 22%, a novel observation.

"This finding is not evident from previous clinical trials, where intravitreous injectables were not widely used," said lead author Nam Hoon Kim, MD.

"These results suggests that fenofibrate may delay or prevent diabetic retinopathy progression in patients with type 2 diabetes," he asserted while presenting the findings at this year's European Association for the Study of Diabetes (EASD) Annual Meeting.

Kim explained the critical importance of early detection and intensive management of diabetic retinopathy but added that therapeutic strategies, especially for the early stages of the disease, have been limited.

"Optimal glycemic and blood pressure control are still the mainstay of medical management in patients with diabetes to prevent or delay diabetic retinopathy," said Kim, associate professor of endocrinology and metabolism at Korea University College of Medicine, Korea University Anam Hospital, South Korea.

His observational, propensity-matched study took a real-world perspective and aimed to determine whether fenofibrate therapy is beneficial in preventing progression of diabetic retinopathy in patients with type 2 diabetes also treated with statins.

Moderator Thomas Nyström, MD, professor of medicine at the Karolinska Institute, Stockholm, Sweden, commented on the work.

"This was an excellent epidemiological study, showing that fenofibrate rescued the eyes from [the effects of] diabetic retinopathy."

"But I seldom use the combination of fenofibrate plus statins," he continued. "The FIELD study showed some positive results, but I think clinicians don't feel fully convinced of fenofibrate, especially compared to statins. We also have PCSK9 inhibitors, but they are very expensive, and the patient qualifying criteria are limiting."

"This study is observational, so the evidence level is not very high and we cannot write guidelines based on this. We need a randomized controlled clinical trial," Nyström stressed. "As a clinician, I know that adding fenofibrate to statins can cause side effects, and for this reason, I'd be cautious."

Propensity-Matched Cohorts From Large Korean National Database

For the study, patients with type 2 diabetes were drawn from a cohort comprised of all South Korean citizens (approximately 50 million) who were at least 30 years of age and had received statins for more than 90 consecutive days after diagnosis. They were randomized 1:2 (statin plus fenofibrate or statin only) such that there were data for 23,692 and 46,223 completers for the analysis, respectively.

A particular strength of the study was the breadth of propensity-matching, which was used to limit bias and confounding. Among the many variables used for matching were age, sex, diabetes duration, socioeconomic status, body mass index (BMI), fasting glucose, systolic blood pressure, pre-existing cardiovascular disease, and baseline low-density lipoprotein (LDL) cholesterol.

Baseline characteristics included average age of approximately 55 years, diabetes duration of 5.2 years, BMI of 26.7 kg/m2, and mean LDL cholesterol of 2.6 mmol/L. Overall, 66%-67% of participants were men, 37%-38% had pre-existing cardiovascular disease, and approximately 28% had diabetic retinopathy.

A composite primary outcome of diabetic retinopathy progression was used, which consisted of events relating to vitreous hemorrhage, vitrectomy, laser photocoagulation, intravitreous injection therapy, and retinal detachment.

Rate of Diabetic Retinopathy Progression Lower With Combination

The incidence rate for diabetic retinopathy progression was 14.3 per 1000 person-years in the statin-only group and 12.7 per 1000 person-years in the statin plus fenofibrate group, with a hazard ratio (HR) favoring the combination group (HR, 0.89; P = .001).

Over the 10-year follow-up, Kim reported a hazard ratio for the cumulative incidence for diabetic retinopathy progression of 0.89 (P = .001) favoring patients on statin plus fenofibrate over statin alone.

Risk of vitreous hemorrhage was also lower in the statin plus fenofibrate group compared with the statin only group (HR, 0.87; P = .008), as was the incidence of laser photocoagulation (HR, 0.89; P = .022) and intravitreous injection therapy (HR, 0.78; P = .003).

Kim and colleagues also analyzed the data according to whether patients had baseline retinopathy or not.

"We found evidence of fenofibrate benefit in those who had baseline retinopathy [OR, 0.86; P = .001], but not in those who didn't have baseline retinopathy [OR, 0.9; P = .145]," he reported.

Regarding adverse events, Kim remarked that "there was no significant increase or decrease between the two groups."

Cardiovascular deaths were also significantly lower in the fenofibrate group [HR, 0.55; P = .003] over the 10-year follow-up.

Existing Guidelines and Study Findings Are Mixed

Existing guidelines for diabetic retinopathy recommend timely intervention with laser photocoagulation or intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents.

Fenofibrate is approved by the US Food and Drug Administration to treat patients with hypertriglyceridemia, primary hypercholesterolemia, or mixed dyslipidemia; the drug showed benefit in diabetic retinopathy in several trials some years ago.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study and Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial demonstrated the benefit of fenofibrate in reducing the effects of diabetic retinopathy.

In the FIELD study, fenofibrate reduced the risk of laser treatment by around 30% compared with placebo, said Kim.

And in the ACCORD Eye study, fenofibrate reduced the risk of diabetic retinopathy progression by 40% (odds ratio, 0.6; P = .006), Kim remarked.

Earlier this year, a large database study published in JAMA Ophthalmology, as reported by Medscape Medical News, showed that fenofibrate was associated with a reduced risk of progression to vision-threatening forms of diabetic retinopathy.

Fenofibrate was approved for the prevention of worsening of diabetic retinopathy in Australia back in 2013.

Professional society guidelines have been inconsistent with respect to fenofibrate in diabetic retinopathy, but the American Diabetes Association Standards of Medical Care in Diabetes — 2022 guidelines note that "in patients with dyslipidemia, retinopathy progression may be slowed by the addition of fenofibrate, particularly with very mild nonproliferative diabetic retinopathy at baseline."

Kim and Nystrom have reported no relevant financial relationships.

EASD 2022. Presented September 21, 2022. Abstract 125.

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