Statins, Fibrates Lower Diabetic Retinopathy Risks in Diabetes

The use of lipid-lowering medication with fibrates, including fenofibrate (Lipidil, Abbott), and statins reduces not only the incidence of diabetic retinopathy in patients with type 2 diabetes but also the need for treatment in those who already have the condition, indicates a real-world Japanese study.

Ryo Kawasaki, MD, MPH, PhD, Department of Vision Informatics (Topcon), Osaka University Graduate School of Medicine, Japan, and colleagues retrospectively analyzed health claims data on almost 85,000 patients with type 2 diabetes.

The results, published in the October issue of Diabetes, Obesity and Metabolism, show that the incidence of diabetic retinopathy was reduced by around 23% with the use of lipid-lowering medication, and fibrates and statins were similarly effective.

And the need for any diabetic retinopathy treatment among patients with type 2 diabetes who already had the complication was reduced by 35% with lipid-lowering medication, and the need for laser photocoagulation and vitrectomy was reduced by 35% and 52%, respectively.

The results follow data from the ACCORD study, which showed that combining fenofibrate with a statin reduced the rate of progression of diabetic retinopathy, and an analysis of the FIELD study indicated that fenofibrate reduced the need for laser treatment of diabetic retinopathy (Lancet. 2007;370:1687-1697).

Indeed, in 2013 fenofibrate was given its first, and to date only, approval in a major market — Australia — to slow the progression of existing diabetic retinopathy in people with type 2 diabetes.

Kawasaki noted, however, that although "fenofibrate or fenofibrate on top of statins have been shown to reduce risk of progression, it has not been well elucidated if lipid-lowering medication is beneficial to the incidence of diabetic retinopathy."

He told Medscape Medical News: "Our study is suggesting that lipid-lowering medication is beneficial for both the incidence and progression of diabetic retinopathy."

However, he added that "this is an observational study and limited to health claims data without clinical quantitative variables such as glucose level or severity of retinopathy," and he called for more studies on this "promising topic."

Clinical Trial Needed, but Challenging, for Fibrates in Diabetic Retinopathy

Kawasaki underlined that it is not clear from the current study whether the findings can be ascribed to the specific effect of fenofibrate, or fibrates in general, as "we did not separate fenofibrate from other types of fibrates, mainly due to a relatively small number of patients."

He nevertheless said that given that fibrates, or fenofibrate in particular, "might have pleiotropic effects in addition to the lipid-lowering effect, we are expecting that this area of research becomes more active."

He pointed to the recent approval in Japan of pemafibrate (Parmodia, Kowa Company), which is a more selective peroxisome proliferator-activated receptor alpha (PPAR-α) modulator than conventional fibrates.

"This might have potential benefit for diabetic retinopathy," he said, "for which we believe a clinical trial is warranted."

Kawasaki added that the prevention of diabetic retinopathy with lipid-lowering medication is "quite promising in theory and there is supportive clinical evidence; however, it is also challenging to conduct a new trial to show the beneficial effect of statins/fibrates, given most patients with diabetes are already on those medications."

Lipid-Lowering Reduces Incidence of Diabetic Retinopathy in Real-World

He and his co-authors say that, although there appears to have been a decline in both the incidence and prevalence of diabetic retinopathy in developed countries, and the effective management of glucose levels and hypertension can prevent or delay it, "a residual risk" remains.

This is purported associated with dyslipidemia, specifically high cholesterol and triglyceride levels, although they note the evidence for this association is “inconsistent” and not as strong as that for diabetic kidney disease.

And as data on this is mainly from clinical trials, they set out to determine whether lipid-lowering medication reduces the risk of diabetic retinopathy and the need for treatment in a more real-world setting.

They gathered information from the health claims database of the Japan Medical Data Center, Tokyo, on adults with a diagnosis of type 2 diabetes or unspecified diabetes and a prescription for a glucose-lowering medication from 2005 to 2017.

They divided the claims into a baseline period of 2005 to 2013 and a follow-up period of 2014 to 2017.

The participants were divided into two cohorts: one that was diabetic retinopathy-free during the baseline period to determine the incidence of diabetic retinopathy during the follow-up period, and the second which consisted of individuals diagnosed with diabetic retinopathy during the baseline period. The latter group was recruited to determine the incidence of diabetic macular edema and the use of diabetic retinopathy-related treatments during the follow-up period.

The team reports that 69,070 individuals were included in the first cohort.

Of these, 20.9% were prescribed standard statins, such as simvastatin and pravastatin, and 79.1% "strong" statins, which included atorvastatin and rosuvastatin. In addition, 54.4% were prescribed bezafibrate and 45.5% fenofibrate.

Patients given lipid-lowering medication were significantly more likely to be women and older, have a longer duration of diabetes and more comorbidities, and be treated with insulin, antihypertensives, and anticoagulants than those not prescribed the medications (P < .001 for all).

During the 3-year follow-up, 7110 individuals developed diabetic retinopathy.

Lipid-lowering medication was associated with a significantly reduced incidence of diabetic retinopathy, with 7.4% of patients treated with the drugs developing the complication versus 11.4% of patients not treated (P < .001).

Logistic regression analysis revealed that lipid-lowering medication was associated with a significantly reduced risk of developing diabetic retinopathy, at an odds ratio (OR) of 0.77 (P < .001).

Both statins and fibrates were separately and independently associated with a reduced risk of diabetic retinopathy, at weighted ORs of 0.79 (P < .001) and 0.78 (P < .003), respectively.

Likelihood of Needing Treatment If Patients Had Diabetic Retinopathy

For the second cohort, 15,738 individuals were selected from the claims database who had diabetic retinopathy at baseline. Of those, 347 developed diabetic macular edema within 3 years, for a rate of 1.2% of patients treated with lipid-lowering medication vs 2.7% of those not treated (P < .001).

Lipid-lowering medication was linked to a significant reduction in the risk of developing diabetic macular edema during follow-up, at an OR of 0.41 (P < .001), as was statin use (OR, 0.38; P < .001) and fibrate use (OR, 0.27; P = .04) individually.

Patients with diabetic retinopathy given lipid-lowering medication were also significantly less likely than those not given the drugs to undergo any diabetic retinopathy-related treatment in general (P < .001), and laser photocoagulation (P < .001) and vitrectomy (P = .007) in particular.

Lipid-lowering medication overall was associated with a significantly reduced risk of receiving treatment for diabetic retinopathy, at an OR of 0.65 (P = .002), as were statins individually (OR, 0.62; P = .001) and fibrates (OR, 0.41; P = .018).

Although lipid-lowering medication was, overall, associated with a reduced risk of laser photocoagulation, at an OR of 0.65 (P = .013), only statin use was, separately, associated with a significant risk reduction (OR, 0.56; P = .04).

A similar pattern was seen for vitrectomy.

Noting that the results could be affected by confounding factors because of the nature of the data source, the team says: "These findings were consistent with the results of clinical trials in patients with diabetic retinopathy who required diabetic retinopathy treatment."

"Our observation further expanded the possibility that lipid-lowering medication can reduce the risk of developing diabetic retinopathy and reduce the need for diabetic retinopathy-related treatment in a relatively short duration of diabetes."

The study was supported by research grants provided by Novartis Pharma and Pfizer, Japan. The authors have reported no relevant financial relationships.

Diabetes Obes Metab. 2018;20:2351-2360. Abstract

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