Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults in the United States, affecting an estimated 20 million Americans.¹ It is associated with findings of drusen or retinal pigment epithelium (RPE) abnormalities in early stages, while choroidal neovascularization (CNV) and/or geographic atrophy (GA) define the late stage. Although a minority of patients are affected by late stage AMD (an estimated 1.49 million Americans in 2019),¹ CNV and GA pose the greatest concern to retina specialists due to the debilitating impacts that they can both have on central vision. Wet AMD, hallmarked by CNV, accounts for 80% to 90% of all blindness amongst patients with any form of AMD, while GA causes irreversible loss of visual function.² Hence, preventing or slowing the development of AMD has emerged as a major research focus within the retina community.

Within the past 2 decades, the management of wet AMD has undergone a revolution due to the emergence of intravitreal agents that act against vascular endothelial growth factor (anti-VEGF agents). However, recurrent injections for AMD represent significant psychosocial, time, and financial burdens to patients and their caregivers.³ Additionally, outside of the strictly controlled protocol of a clinical trial environment, many patients may be undertreated with anti-VEGF therapy and experience worse visual outcomes.⁴ Treatments for the dry form of AMD are comparably even more limited. Until the recent Food and Drug Administration approval of intravitreal pegcetacoplan injection (Syfovre; Apellis Pharmaceuticals), no treatment had existed to slow or reverse the effects of GA or dry AMD.⁵ Instead, retina specialists have primarily been limited to considering a formulation of high-dose antioxidants and zinc supplementation that was shown to modestly slow the progression from intermediate to advanced AMD in the Age-Related Eye Disease Study (AREDS) and AREDS2 clinical trials.^6,7 Although therapeutics to treat both the dry and wet forms of AMD have expanded, there remains an unmet need to address the growing burden AMD will impose on patient quality of life and the health care economy as the global population continues to age. This article explores the possible roles of systemic medications in addition to lifestyle interventions for delaying the onset or slowing the progression of AMD.

METFORMIN

Metformin is a common oral medication used to treat type 2 diabetes. It has been explored as an agent that could prevent AMD due to its potential antiaging properties and interactions with cellular pathways that modulate aging.⁸ In preclinical studies using animal or in vitro models, it has been suggested that metformin protects against AMD through antiangiogenic, anti-inflammatory, and antioxidative properties that prevent CNV formation and damage to the RPE.⁹ Retrospective clinical studies examining the relationship between metformin use and AMD development have produced inconsistent yet encouraging results.

In a nationwide case-control study of more than 300,000 AMD cases and matched controls, Blitzer et al found that metformin use at low and moderate doses was associated with a mild 5% to 10% reduction in the odds of AMD development, and this protective effect was greater in individuals without diabetic retinopathy compared to those with diabetic retinopathy.¹⁰ Additional retrospective studies, albeit with smaller sample sizes, have identified that metformin reduces the odds of AMD development from 30% to 46%.^11-13 However, other retrospective clinical studies have failed to show a benefit to metformin use in preventing AMD.^14-16 These differences are likely attributable to subtle differences in study populations and study design.

Considering its relatively benign side-effect profile, widespread availability, and potential protective effects in other age-related diseases, metformin may be a candidate for targeting AMD. Further research, however, is necessary to determine the clinical implications of these observational findings, especially the effects of metformin on AMD development in nondiabetic patients. This is an unexplored population. Blitzer et al. demonstrated that the protective effect of metformin is diminished in individuals with diabetic retinopathy, generally associated with more severe diabetes, naturally raising the question of whether metformin use holds even greater promise among nondiabetic patients. Moreover, differentiating between dry and wet forms of AMD and establishing ideal metformin dosing require further investigation. Ongoing clinical trials, such as a phase 2 trial examining metformin’s impact on AMD progression to GA in nondiabetic patients, will offer valuable insights into the potential use of metformin as a therapeutic agent in AMD.¹⁷

LIPID-LOWERING AGENTS

Statins are a class of lipid-lowering medications commonly prescribed for cardiovascular disease. Their potential association with AMD prevention has been studied due to the parallels between cardiovascular disease and AMD, such as the shared risk factors of smoking, hypertension, and obesity, in addition to the lipid-rich drusen of AMD that mimic atherosclerotic burden. However, findings from population-level studies exploring the relationship between statin use and AMD have been inconclusive to date.¹⁸ Notably, among AREDS2 participants with bilateral large drusen or unilateral large drusen and late AMD in the fellow eye, Al-Holou et al found that statin use did not have any association with AMD progression.¹⁹ However, among the subgroup of patients with bilateral large drusen, statin use was protective against progression to advanced AMD.¹⁹ The majority of studies investigating the association between statin use and AMD have failed to differentiate between low-intensity and high-intensity statin exposure.

The best evidence for statins to treat AMD currently stems from a single randomized controlled trial (RCT) and a small case series. An RCT by Guymer et al enrolled 114 patients with normal lipid profiles and either bilateral intermediate AMD or unilateral advanced AMD with nonadvanced AMD in the fellow eye.²⁰ Compared to placebo-treated patients, those with bilateral intermediate AMD who were assigned to 40 mg of daily simvastatin (a low-intensity formulation) had a significant reduction in AMD progression at 3 years of follow-up. A case-series performed by Vavvas et al included 26 patients with AMD and multiple large drusen who were assigned to 80 mg daily atorvastatin.²¹ At 12 months of follow-up, 10 patients had regression of drusen with improvements in visual acuity, and no patients progressed to wet AMD. While there were no controls in this open-label study, it did suggest that a high-intensity statin may ameliorate drusen. Further research is required to clarify the role of statins in AMD prevention or progression and elucidate the underlying mechanisms involved. A novel, high-dose reformulation of atorvastatin is currently being prepared for study in a clinical trial of patients with intermediate AMD and will likely provide the best evidence for the efficacy of this class of medication.²²

LEVODOPA

Studies have also explored the association between levodopa, used to treat movement disorders like Parkinson disease, and AMD development. Levodopa stimulates the expression of pigment epithelial derived factor (PEDF), which has antiangiogenic properties and reduces VEGF levels, the primary target of wet AMD therapies.²³ In a retrospective study, Brilliant et al found that those exposed to levodopa were less likely to develop dry or wet AMD, and those who went on to develop AMD did so at a later age in life.²⁴ Hyman et al also found reduced conversion to wet AMD and a decreased need for intravitreal injections in eyes exposed to levodopa.²⁵ Furthermore, in a small proof-of-concept study, Figueroa et al describe improvements in visual acuity and the need for fewer anti-VEGF injections in patients with newly diagnosed wet AMD who received levodopa.²⁶ A clinical trial of levodopa in patients at high risk of conversion to wet AMD is clearly warranted, as there is a well-established and plausible mechanism of action in addition to strong preclinical data.

LIFESTYLE INTERVENTIONS

The paucity of treatments for AMD warrants retina specialists to carefully consider how certain lifestyle interventions may modulate AMD disease activity. Although the relationships between various comorbidities and AMD are inconsistently described in the literature, optimization of systemic conditions, such as hypertension, hyperlipidemia, and obesity, is an important consideration, because these may increase the risk of AMD.²⁷ Finally, regular physical exercise is an additional important aspect of patient counseling, and, in combination with smoking cessation and a healthy diet, these lifestyle factors may significantly reduce the risk of developing or experiencing progression of AMD.²⁸

An emerging area of focus is the role of overall nutritional intake in AMD. While a wealth of single nutrients, including carotenoids, vitamins, fatty acids, carbohydrates, and minerals may abate AMD severity, findings in this realm are inconsistent.²⁹ Furthermore, evidence for dietary supplements as primary prevention of AMD seems limited, and an overall healthy diet may be the best strategy to minimize the risk of developing AMD.²⁹ A Western-style diet, rich in red meat and high in fat, has been linked to increased odds of AMD development.³⁰ The Mediterranean diet, on the other hand, emphasizes a foundation of plant-based foods, such as vegetables, whole grains, fruits, and legumes, with moderate amounts of dairy, fish or olive oil rich in omega-3 fatty acids, and seafood, while red meats are consumed rather infrequently. Emerging evidence supports that adherence to a Mediterranean-style diet may be an important behavioral intervention in patients with or at risk of AMD.

Analysis of AREDS participants revealed that patients in the tertile with the greatest adherence to a Mediterranean diet had a 26% decreased risk of progression to advanced AMD compared to patients in the lowest tertile of adherence.³¹ Meanwhile, combined analysis of AREDS and AREDS2 participants with the greatest adherence to a Mediterranean diet revealed a 29% decreased risk of progression to GA and a 16% decreased risk of progression to wet AMD, and there was evidence of a dose-response relationship between adherence and progression to these forms of advanced AMD.³² Notably, these protective effects were independent of oral supplements used in either study, suggesting that a Mediterranean diet has an additional and harmonious role in patients with intermediate AMD. Furthermore, the authors reported that patients had a 21% decreased risk of progression to large drusen, which presents an encouraging development that a Mediterranean diet could also protect against intermediate AMD.³² Additional prospective European cohorts have corroborated these data, finding a 41% reduced risk of incident AMD in patients following a Mediterranean diet.³³ These findings may possibly be explained by the connections between diet and the gut microbiome, with increasing evidence that patterns of food consumption impact the composition of the gut microbiome.³⁴ In turn, alterations to the gut microbiome may propagate to the retina along a proposed “gut-retina axis,” thereby explaining the important links between AMD and diet.³⁵

IMPLICATIONS FOR RETINA SPECIALISTS

The role of systemic medications in managing or preventing AMD is currently unclear. Retina specialists should advise their patients on the scientific evidence for and against any of these medications, particularly incorporating data from clinical trials if and when they become available. However, initiating any systemic medication for preventing or delaying the progression of AMD is premature and not in line with evidence-based medicine at this time.

The use of AREDS2 vitamin and mineral supplements should be advised in all patients with intermediate AMD or in patients with late AMD and early AMD in the fellow eye.⁷ However, these supplements have not been shown to have a benefit for patients with early AMD or those at risk of AMD. These patients should, instead, be advised to optimize medical comorbidities and undergo lifestyle changes around diet, physical activity, and smoking cessation. Adoption of a Mediterranean diet is a particularly promising modifiable behavior, as it not only protects against debilitating forms of advanced AMD but also may have a benefit for intermediate AMD. Finally, conversations with patients about lifestyle interventions should always be supplemented by the full spectrum of scientific evidence, preferably from randomized trials or longitudinal prospective studies. RP

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