Diabetic Retinopathy Tx: a Role for Fibrates and Statins?

RETINA CLINICAL UPDATE

Diabetic Retinopathy Tx: A Role for Fibrates and Statins?

oday’s ophthalmologists have opment of atherosclerosis, and the good treatment options for the drugs are already prescribed for many Tadvanced stages of diabetic patients with diabetes, said Dr. Chew. retinopathy (DR)—laser, intravitreal Fenofibrate—which is sometimes injection, and vitrectomy—said Eugene prescribed to patients who can’t take Yu-Chuan Kang, MD, at the Chang statins—also can lower LDL. Gung Memorial Hospital in Taiwan. Moreover, both fibrates and statins However, these treatments can be may have multipronged effects be- onerous, invasive, or costly. “We need yond lipid control, said Dr. Kang. something with few side effects that’s “These medications may also influence inexpensive and can be given widely,” inflammation, angiogenesis, and cell noted Emily Y. Chew, MD, at the NEI. survival.”2-4 Statins and fibrates to the rescue? Interestingly, the FIELD and AC- Could lipid-lowering drugs such as CORD-EYE studies did not confirm PROGRESSION. Neovascularization of statins and fibrates fit the bill? Certain- the effect of fenofibrate on DR to be the optic disc along with hard exudates ly, they are widely available and cost- through lipid lowering, Dr. Chew said. and scattered retinal hemorrhages, effective. “You can buy a lifetime supply “We don’t actually know the mecha- seen in a patient with proliferative DR of simvastatin or fenofibrate for the cost nism of action for fenofibrate in DR.” and DME. Some evidence suggests that of one vial of our intravitreal injec- Making the case. “Years before we lipid-lowering medications slow DR tions,” said Sunir J. Garg, MD, at Wills had statins, we saw a good correlation progression. Eye Hospital in Philadelphia. They do between lipids and eye disease in the carry a risk of side effects, however Early Treatment Diabetic Retinopathy lipid-lowering medicines have an effect (see “Caution: Drug Side Effects”). Study (ETDRS),” Dr. Chew said. “The on DR, said Dr. Garg, but it’s hard to Statins and fibrates are back in the higher the lipids, the higher the risk of tease out the size and scope of that spotlight, thanks to a recent retrospec­ retinopathy.” With the advent of better effect. “Does it prevent diabetic eye dis- tive study conducted in Taiwan by Drs. lipid control, ophthalmologists are ease? Most of the studies right now say Garg and Kang and their coauthors. less likely to see eyes filled with hard no,” he said. “Is it useful in preventing They investigated the association exudates, she added. preexisting diabetic eye disease from between statin therapy and the devel- The Wisconsin Epidemiology Study getting worse? Potentially.” opment of DR in patients with diabetes of Diabetic Retinopathy demonstrated Approved in Australia. Although and dyslipidemia and found that statin that people with diabetes and visible no country has approved the use of use was associated with a decreased lipid deposits in their retinas had higher statins for DR, said Dr. Kang, Australia prevalence of diabetic retinopathy.1 serum lipid levels. It also found that in- approved fenofibrate for this indication creasing DR severity and hard exudates in patients with type 2 diabetes in 2013, Laying the Groundwork corresponded with increasing serum following completion of the Fenofibrate Statins help lower low-density lipo- cholesterol, Dr. Garg said. Intervention and Event Lowering in protein (LDL), a culprit in the devel- Other studies have indicated that Diabetes (FIELD) study5 and the Action to Control Cardiovascular Risk in Di- abetes-Eye (ACCORD-EYE) Study6— BY ANNIE STUART, CONTRIBUTING WRITER, INTERVIEWING EMILY Y. CHEW, two randomized clinical trials that

Sunir J. Garg, MD Garg, Sunir J. MD, SUNIR J. GARG, MD, AND EUGENE YU-CHUAN KANG, MD. showed fenofibrate to be beneficial in

EYENET MAGAZINE • 27 the treatment of DR. Thus far, however, no other countries have followed suit. Caution: Drug Side Effects Three Key Studies Both fibrates and statins can cause muscle aches and liver problems, Dr. Garg FIELD. This study, published in 2007, noted. Other side effects linked to both drugs include headaches, abdominal examined the effects of fenofibrate ver- pain, and nausea and vomiting. In the past, there were concerns that combin- sus placebo in 9,795 patients with type ing fenofibrates with statins would exacerbate muscle breakdown and fatigue, 2 diabetes. The researchers found that, said Dr. Chew. “However, in the ACCORD-EYE Study, we found very little of in addition to slowing progression of that. If we saw an increase in creatinine, we adjusted the dose of the drug and preexisting DR, 200 mg of fenofibrate the numbers went back down.” per day reduced the occurrence of dia- To take fenofibrate successfully, a patient needs to have regular blood work betic macular edema, Dr. Garg said. to monitor the liver and kidney, said Dr. Garg. “In cases like this, we would Moreover, use of laser was reduced typically ask the cardiologist or internist to help us.” The key, said Dr. Chew, by nearly a third in these patients, said is to communicate with the doctor giving the medical care. If he or she is Dr. Chew. “In fact, all microvascular unwilling to do the blood work, you can do it yourself. disease benefited, with a clear beneficial effect on the kidneys and a reduction in foot ulcers, for example.” However, fenofibrate had no effect on cardiovas- er laser, injections, or surgery.” The their Taiwanese study is limited by its cular disease outcomes. researchers also found a greater associa- retrospective cohort design. ACCORD-EYE. This study—a sub- tion between a decrease in DR risk and Need for bigger studies. What is study of the parent ACCORD study— the use of higher doses and longer du- really needed, said Dr. Garg, are larger compared the results of simvastatin ration of statin therapy, said Dr. Kang, randomized controlled trials, with plus fenofibrate to those achieved with which emphasizes the importance of sufficient power, conducted in patients simvastatin plus placebo. The outcomes, medication adherence. with preexisting DR of various levels published in 2014, were similar to those of severity. Ideally, too, those patients found in FIELD, said Dr. Chew, who Challenges in Moving Forward would be monitored with current chaired ACCORD-EYE. Nuances in disease development. One imaging technologies. “But as of now, Unlike in the FIELD study, however, challenge with these types of studies is there’s not a large incentive for a big DR was the primary microvascular the difficulty of detecting changes in pharmaceutical company to sponsor outcome in ACCORD-EYE—and the the diabetic eye, said Dr. Garg. This was this type of trial,” he said. “The drugs addition of fenofibrate to statin therapy especially true before sophisticated are inexpensive, and so no company is demonstrated benefits for the kidneys imaging like optical coherence tomog- really pushing this.” and feet, but not for the heart, she said. raphy (OCT) became available. “In Indeed, Dr. Chew said, what’s The benefit of fenofibrate with regard addition, if a person has no diabetic eye necessary to really capture the interest to slowing DR progression was greatest disease at baseline and their sugar control and acceptance of ophthalmologists is in patients with mild retinopathy. is reasonable, their rate of dev­eloping another study conducted by ophthal- ACCORD-EYE “found that feno- eye disease may not be fast,” he said. “In mologists to test fenofibrate for this fibrate plus a statin is better than a a two- to four-year period, we may not disease. A previous attempt to initiate statin alone,” Dr. Kang said. Within see a lot of difference in their disease.” such a trial by the Diabetic Retinopathy four years, 12% of the control group On that note, Dr. Garg pointed out Clinical Research Network (DRCR. progressed two or more steps on the that both FIELD and ACCORD-EYE net) fell by the wayside, she said. “We’re ETDRS scale, compared with 10.6% showed benefit for people who already hoping it may yet happen,” she said, in the statin group and 6.5% in the had retinopathy, but neither showed explaining that such a trial “would statin-fibrate group.6 This translated benefit for those without retinopathy at have the potential to engage 150 clinics into about a one-third reduction in the baseline. This may have been because of in the network and hundreds or thou- progression of diabetic retinopathy. the length of time needed to track the sands of patients.” Taiwanese study. This population- impact of treatment (as well as the time based cohort study, published earlier needed for retinopathy to develop), Dr. Current Recommendations this year, was conducted among 37,894 Chew said. Given the evidence to date—and the Taiwanese patients with type 2 diabetes Need for better data. “Although questions that remain—should clini- and dyslipidemia. Of these, half had some of the DR data have been com- cians incorporate lipid-lowering drugs taken statins.1 pelling, they are not clean and airtight into their treatment plan for patients People taking statins were less likely enough to really hit home with your with diabetes? to have DR, said Dr. Garg. “The study typical ophthalmologist or retina Stay the course. “I would not rec- also showed that statin use was asso- specialist,” Dr. Garg said. In addition, ommend a change in practice at this ciated with fewer treatments—wheth- Drs. Garg and Kang acknowledged, time,” said Dr. Garg. Controlling blood

28 • NOVEMBER 2019 sugar and blood pressure is what’s most Diabetes statements. Although the help­ful for patients, he said. These two Academy’s Preferred Practice Pattern Coming in the next strategies “dwarf anything else in terms on DR does not contain a specific ® of the magnitude of importance—not recommendation for fenofibrate,8 the just for eyeballs but for overall health.” American Diabetes Association Position Glucose control. Tight glucose con- Statement notes that “. . . there are suffi- trol can reduce the risk of eye disease cient data to suggest developing collab- by as much as 70%, said Dr. Chew— oration between the ophthalmologists Feature and with type 2 diabetes, it can reduce (eye care providers) and the medical Adopting the Evidence its progression rate by a third. physician to consider this treatment for Why it can be difficult Blood pressure control. In ACCORD- people affected with diabetic retinop- to adopt the latest evi- EYE, the researchers didn’t find a athy.”9 dence-based practices, treat­ment effect with blood pressure and how to keep your clinic 1 Kang EY-C et al. JAMA Ophthalmology. 2019; control, Dr. Chew said. However, other current. Plus, a few study 137(4):363-371. studies have. For example, the United findings worth adopting 2 Noonan JE et al. Diabetes. 2013;62(12):3968- Kingdom Prospective Diabetes Study now. 3975. (UKPDS) showed that, after nine years 3 Ioannidou E et al. World J Diabetes. 2017;8(1): Clinical Update of follow-up, tight blood pressure 1-6. Cataract New IOLs devel- control (target pressure of <150/85 mm 4 Gong Y et al. EBioMedicine. 2016;13:201-211. oped specifically for Hg), compared with less tight control 5 Keech AC et al. Lancet. 2007;370:1687-1697. patients with AMD. (target pressure of <180/105 mm Hg), 6 Chew EY et al. Ophthalmology. 2014;121(12): reduced the progression of DR and Refractive An update on 2443-2451. reduced the risk of vision loss by 47%.7 SMILE: Where are we now? 7 UK Prospective Diabetes Study Group. BMJ. Lipid control. Despite the dearth of 1998;317(7160):703-713. Pearls randomized trials focusing on lipids 8 American Academy of Ophthalmology Retina/ Argus II A look at the and DR, Dr. Kang recommended that Vitreous Panel. Preferred Practice Pattern Guide- FDA-approved epiretinal ophthalmologists emphasize lipid lines Diabetic Retinopathy. aao.org/ppp. Accessed implant that is in use by 350 control in patients who have diabetes. Aug. 6, 2019. people. “Ophthalmologists should encourage 9 Solomon SD et al. Diabetes Care. 2017;40:412- these patients to not only have regular 418. Savvy Coder eye exams but also systemic evalua- Audit Alert! What do audi- tions, including [analysis of] serum Dr. Chew is director of the Division of Epidemi- tors look for? Six practices lipid levels.” ology and Clinical Applications and the deputy to avoid. Adherence. If medication is pre- clinical director at the NEI in Bethesda, Md. scribed, it’s important that the patients, Relevant financial disclosures: None. Practice Perfect family, and doctors make sure the Dr. Garg is a partner with Mid Atlantic Retina, Beyond Private Equity patient takes it regularly, Dr. Kang said. attending physician on the Retina Service at Wills Six options for scaling up “Without medical adherence, the dis- Eye Hospital, and professor of ophthalmology without selling to private ease can’t be well controlled.” at Sidney Kimmel Medical College at Thomas equity. Consider fenofibrate? At this time, Jefferson University in Philadelphia. Relevant statins are very well accepted, said Dr. financial disclosures: None. Blink Chew, and most patients with diabe- Dr. Kang is chief ophthalmology resident at Take a guess at the next tes are put on them. “The main drug Chang Gung Memorial Hospital, Chang Gung issue’s mystery image. in question is fenofibrate, especially University, in Taoyuan, Taiwan. since studies have not shown that it Relevant financial disclosures: None. helps with cardiovascular disease,” she For full disclosures, see this article at aao.org/ For Your Convenience said. “For this reason, endocrinologists eyenet. These stories also will be and other physicians are reluctant to available online at prescribe fenofibrate. And ophthalmol- aao.org/eyenet. MEETINGS ON DEMAND ogists are also reluctant to prescribe If you missed the it because of the required medical FOR ADVERTISING INFORMATION special section on monitoring.” diabetes at Retina Mark Mrvica or Kelly Miller However, in collaboration with Subspecialty Day M. J. Mrvica Associates Inc. a patient’s internist, cardiologist, or 2019, go to aao.org/ 856-768-9360 other medical physician, Dr. Chew has annual-meeting/ [email protected] prescribed fenofibrate for some of her aao-on-demand. patients with DR.

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