Planning for AREDS2

Consider the latest data as the retina community prepares for the landmark findings of a long-awaited controlled trial on ocular nutrition.

By Seenu M. Hariprasad, MD

By now, most of us accept that ocular vitamins can change the course of AMD, improving quality of life and saving millions of dollars associated with treatment and lost productivity. What we do not fully understand are the precise mechanisms of action of vitamin therapy and what role it may play in various stages of disease progression and various risk levels.

Excitement is building as we await the results of the Age-Related Eye Disease Study 2 (AREDS2), a 5-year controlled, randomized trial involving 4,203 subjects at 82 centers. The results of AREDS2 will be available in a few months, setting the stage for more than a dozen groundbreaking reports after the data is released. The complex array of findings will require our careful consideration. In preparation for AREDS2, I will provide an update of the latest thinking in the ocular vitamin landscape.

AMD STRESSES RESOURCES

AMD, the leading cause of severe vision loss in people aged 50 years and older in developed countries,¹ continues to take a heavy toll on our aging population and our strained healthcare system. This debilitating disease affects an estimated 10 million people in the United States,² a number that is expected to increase by as much as 50% by 2020.³ Although we can point to great progress associated with the development of sight-preserving anti-vascular endothelial growth factor (anti-VEGF) therapy, these breakthrough treatments have crammed our waiting rooms and more than doubled costs for patient care. The retina community is quickly running out of the resources needed at various levels to treat all of these patients.

A new study of Medicare beneficiaries found that 20.4% of 1,184 people who were diagnosed with dry AMD in 1998 progressed to wet AMD. Between 1999 and 2009, average annual Medicare costs increased from $11,265 to $24,494 for AMD patients who did not progress to wet AMD and from $11,712 to $34,308 in patients who did.⁴

Beyond intravitreal drugs, costs associated with transportation, caregivers’ time off from work, patients’ inability to work and injuries add to the overall economic burden of AMD.

PREVENTIVE THERAPY?

We can’t be certain how much of our problem with AMD could be eliminated by the increased use of ocular nutrition as a preventive measure. But we can safely say that a worthwhile amount is possible, based on the latest evidence (Table 1, next page). The results of AREDS, completed in 2001, showed that a combination of high-dose antioxidant vitamins and zinc demonstrated a 25% reduction of risk for the development of advanced AMD over a median of 6.3 years of follow-up in subjects at high risk (categories 3 or 4). After the study terminated, follow-up showed that the beneficial effects of AREDS supplements persisted at a similar level of protection.

Table 1. AREDS Rate to Advanced AMD With Supplements

Data are shown for the probability of progression to advanced AMD in ≥1 eye in patients with intermediate AMD in the four treatment groups: placebo, antioxidants, zinc or antioxidants plus zinc and advanced monocular AMD (category 3 and 4).

The probabilities of progression to advanced AMD within 5 years in each group were:

■ Placebo: 28%

■ Antioxidants: 23%

■ Zinc: 22%

■ Antioxidants plus zinc: 20%

Reference

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

The primary objective of AREDS2 is to determine if oral supplementation with macular xanthophylls and omega-3 long-chain polyunsaturated fatty acids will decrease the risk of progression to advanced AMD when compared to placebo. The xanthophylls include lutein (10 mg/d) and zeaxanthin (2 mg/d). The omega-3 fatty acids include docosahexaenoic acid (DHA 350 mg/d) and eicosapentaenoic acid (EPA, 650 mg/d). AREDS2 is also studying the effects of these nutritional supplements on moderate vision loss and on the development of cataracts.

A new paper on the design and baseline characteristics of AREDS2 shows that most study participants were classified as having bilateral large drusen/noncentral geographic atrophy (59%).⁵ It is significant to note that the AREDS2 study population (median age, 74 years) is older at baseline than the AREDS population (median age, 69 years), partly because the AREDS2 population includes only persons at high risk for developing advanced AMD. The participants with no or early AMD found in AREDS tended to be younger than those with AMD. In both studies, approximately 96% of the study populations are white. There are similar proportions of women (57%) and smokers (7%) in both studies, as well. In contrast, 44% of the AREDS2 participants are taking a statin-class, cholesterol-lowering drug, whereas only 9% of the AREDS participants were taking this class of drugs.

Figure 1. Fundus photograph showing dry AMD with drusen and RPE changes.

Figure 2. Fundus photograph showing dry (non-exudative) AMD.

Figure 3. Fundus photograph showing advanced dry AMD. Clinicians hope that ocular nutrition can help prevent patients with advanced dry AMD from progressing to wet AMD.

SECONDARY RANDOMIZATION

A key area of interest will focus on how much zinc and beta-carotene will be needed to reduce the risk of AMD. Beta-carotene has been shown to increase the risk of lung cancer in smokers⁶ and, unlike lutein and zeaxanthin, it is not one of the carotenoids naturally found in the eye. The main adverse effect associated with zinc use in AREDS was increased hospitalizations for genitourinary disease, mainly prostate hypertrophy in men.⁷ Because of these factors, the AREDS2 research group is conducting a second randomization to evaluate the possibility of deleting beta-carotene and reducing the level of zinc. All AREDS2 subjects have been required to enroll in the first randomization of lutein/zeaxanthin and omega-3 fatty acids. They are then offered the opportunity to be randomly assigned to the second randomization involving the different doses of the AREDS formulation, including:

■ Original AREDS formulation

■ Original AREDS formulation without beta-carotene

■ Original AREDS formulation with a lower amount of zinc (25 mg)

■ A formulation that includes the combination of lower zinc and no beta-carotene.

The secondary randomization will tell us which formulations offer the most benefit to patients.

OBSERVATIONAL STUDIES

Numerous observational studies, some completed by AREDS researchers, point to high levels of lutein and zeaxanthin decreasing the risk of AMD.⁸ We have also seen evidence that omega-3 fatty acids reduce the risk of AMD.⁹ However, we must await the conclusions of AREDS2 before considering a change in the AREDS formulation, which includes:

■ Vitamin C, 500 mg

■ Vitamin E, 400 IU

■ Beta-carotene, 15 mg

■ Zinc, 80 mg

Editor’s note: This list is not all-inclusive. There are other ocular supplements on the market.

■ Cupric oxide (copper), 2 mg

The AREDS supplements are indicated for patients with extensive intermediate drusen or large drusen (category 3) and advanced AMD in one eye, including either geographic atrophy in the center or neovascular AMD (category 4).

ROLE OF MPOD

Effective treatment of AMD at an early stage is obviously preferred over late-stage administration of anti-VEGF or combination therapy. Early treatment could involve lutein and zeaxanthin, which have been evaluated in terms of their effects on the density of the macular pigment optical density (MPOD). These xanthophyll carotenoids, major components of macular pigment, are believed to help maintain the morphologic and functional integrity of the retina.¹⁰ The supplements are capable of filtering blue light and suppressing reactive oxygen species, possibly protecting against the light-induced oxidative damage that has been implicated in the pathogenesis of AMD.¹¹

The clinical implications of MPOD — and the best ways to measure it — are not entirely clear at this point. However, new research based at Peking University shows that patients benefit when MPOD density is increased.¹² Lutein and zeaxanthin supplements were found to improve MPOD in patients with early AMD, contributing to increased visual function. Researchers concluded that these carotenoids might decrease the rate of AMD progression.

The primary outcome of the Peking study was the MPOD findings. However, important secondary outcomes were visual function variables, including best-corrected visual acuity (BCVA), contrast sensitivity, photorecovery time, and Amsler grid testing results. MPOD increased significantly by a mean +/- standard error of 0.076 +/- 0.022 density unit in subjects receiving 20-mg lutein per day and by 0.058 +/- 0.027 density unit in patients receiving 10-mg/day lutein plus 10-mg/day zeaxanthin per day during a 48-week period. There was a significant dose-response effect for lutein supplementation, and the changes in MPOD from baseline to 48 weeks were correlated negatively with baseline MPOD in all active treatment groups. At 48 weeks, a trend toward improvement was seen in BCVA, and there was a significant between-group difference in contrast sensitivityat 3 and 6 cycles/degree between the 20-mg lutein group and a placebo group. The increase in MPOD related positively to the reduction in the logarithm of the minimum angle of resolution BCVA and the increases in contrast sensitivity at four spatial frequencies.

XANTHOPHYLLS’ EFFECTS ON LATE-STAGE AMD

The Peking researchers recommended future study to evaluate the effect of lutein and zeaxanthin on the incidence of late-stage AMD. However, one meta-analysis found that increased intake of these carotenoids was associated with up to a 26% reduction in the risk of late AMD.¹³ The findings of this study suggest that lutein and zeaxanthin supplementation could effectively prevent the progression of early-stage AMD to late stages (although, oddly enough, no significant relationship between dietary intake of lutein

and zeaxanthin and early AMD was found in this study).

In the Lutein Antioxidant Supplementation Trial II (LAST), researchers tried to discern characteristics that increase MPOD, hoping to identify factors that might differentiate a responder from a nonresponder.¹⁴ Subjects who had the lowest MPOD and greatest need for supplements were most likely to benefit from either the lutein or the lutein plus antioxidant supplementation. The MPOD of those who responded to supplementation continued to increase at 12 months. This finding suggests that effective interventions could re-establish the prophylactic barrrier of MPOD if a deficiency in MPOD is accurately diagnosed.

MPOD analysis is likely to gain wider acceptance in the future as it could act as a potential marker for identifying patients at high risk for dry AMD or act as a valid endpoint for investigating effects of dry AMD interventions. For example, MPOD, which decreases with age, could soon be used as an endpoint to demonstrate how both of these xanthophyll carotenoids can increase MPOD. We may end up evaluating normal ranges, how measurements change over a patient’s life and how the vitamins can reverse age-related change.

KEY QUESTIONS

Identifying risk factors for AMD will also become increasingly important as we look to the future. Do deficiencies of lutein, zeaxanthin and dietary omega-3 fatty acids increase risk? What is the role of counseling on poor diet, obesity, smoking and hypertension? When do vitamins make sense, based on family history, clinical examination, and other factors? Also, we should not forget the emerging science of genetics in AMD. What role should in-office genetic testing play in identifying patients at “high risk” and how should these patients be managed differently from “low-risk” patients?

BOLD NEW FUTURE

As you can see, we have a great deal to consider as the AREDS2 data release quickly approaches. It is an exciting time of rapidly evolving data — data that will only evolve faster in the year ahead, given such new testing modalities as those used to measure MPOD. Our practices and patients should benefit immeasurably if we embrace new findings and move forward with a commitment to improved quality of care.

Dr. Hariprasad is Associate Professor of Ophthalmology & Visual Science, Chief of the Vitreoretinal Service and Director of Clinical Research at The University of Chicago Medical Center. He also directs the Vitreoretinal Fellowship. He is a consultant or on the speaker’s bureau for Optos, Alcon, OD-OS, Bayer, Allergan, Regeneron, and Genentech.

References

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7. Johnson AR, Munoz A, Gottlieb JL, Jarrard DR. High dose zinc increases hospital admissions due to genitourinary complications. J Urol 2007;177(2):639-643.
8. SanGiovanni JP, Chew EY, Clemons TE, et al; for Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol 2007;125(9):1225-1232.
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11. Sasaki M, Ozawa Y, Kurihara T, et al. Neuroprotective effect of an antioxidant, lutein, during retinal inflammation. Invest Ophthalmol Vis Sci 2009;50:1433-1439.
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13. Ma L, Dou HL, Wu YQ, et al. Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis. Br J Nutr 2012;107:350-359.
14. Richer S, Devenport J, Lang JC. LAST II: Differential temporal responses of macular pigment optical density in patients with atrophic age-related macular degeneration to dietary supplementation with xanthophylls. Optometry 2007;78(5):213-219.