In an era of minimally invasive glaucoma surgery and sustained-release implants, one topic is often overlooked but remains clinically relevant to our field and to our patients: nutritional supplements in glaucoma. Approximately one in nine glaucoma patients use complementary and alternative medicine (CAM) specifically for glaucoma, according to a large multicenter cross-sectional survey by Wan et al from 2012.¹ Of these, more than half (62.5%) had not disclosed the use of CAM to their ophthalmologist and many (40.5%) believed the CAM was helping their glaucoma.

Patients are looking for alternatives to compliment traditional glaucoma care, whether they ask us about them or not. It is important for ophthalmologists to feel comfortable discussing the prospects of alternative therapy, such as nutrition supplementation, as we have the ability to guide patients towards safer, reliable and more promising CAM options.

Here are answers to some of the key questions surrounding nutritional supplements.

WHY CONSIDER NUTRITIONAL SUPPLEMENTS?

While our standard of care in glaucoma focuses on lowering IOP, ample evidence suggests the existence of IOP-independent mechanisms of retinal ganglion cell (RGC) death. The continuously growing field of neuroprotection/neuro-enhancement focuses on ways to promote RGC survival (ie, through mitochondrial stabilization or anti-oxidants). Additionally, the vascular theory of glaucoma promotes an interest in substances that help regulate and improve blood flow around the optic nerve head. Promising supplements (Table) may have one or multiple mechanisms by which they could either slow visual field loss progression or reverse functional damage as measured by electrophysiological testing or perimetry.

For each supplement, there is a significant body of literature based on in vitro or animal studies often leading up to clinical studies (though a thorough review of them is beyond the scope of this review).

WHICH ARE MOST PROMISING?

While there is no definitive answer here given the current level of evidence, I personally have found a few supplements to be promising based on a literature review (Table). The listed supplements have had at least one randomized controlled trial (RCT) in humans with some degree of positive outcome, albeit with usually a small sample size. While it is easy to get bogged down in the details, I’ve compiled what was most clinically relevant: dosages, contraindications/considerations and preliminary positive findings, if any.

In addition to these supplements, a long list of others may hold utility in glaucoma, such as taurine, curcumin, alpha-lipoic acid, polyunsaturated fatty acids, flavonoids besides ginkgo, anthocyanins (eg, quercetin, luteolin), palmitoylethanolamide and forskolin.^2-5

WHAT ABOUT MULTI-NUTRIENT FORMULAS?

Patients can sometimes be overwhelmed with the thought of scouting out their own nutrients from reliable sources with recommended dosages. Several multi-nutrient formulations are available, two of which I have described below; notably, both have a few of the nutrients outlined in the Table, amongst many others.

GlaucoCetin (Guardion Health Services) is a modified version of a parent compound GlaucoHealth. It is a medical food, which the FDA recognizes with distinctive nutritional and recognized scientific requirements. The ingredients are known to have anti-inflammatory and antioxidant properties and include: ginkgo biloba extract, citicoline, coenzyme Q10, niacinamide, curcumin, n-acetylcysteine, alpha lipoic acid, grape seed extract, green tea extract, L-taurine, biotin, natural astaxanthin, fiestin, quercetin and luteolin. A small, randomized, double-masked trial of GlaucoHealth vs placebo in glaucoma patients found significant decrease in mitochondrial oxidative stress markers (eg, optic nerve mitochondrial flavoprotein fluorescence and its average curve width) after 1 month of consumption.⁶

Optic Nerve Formula (Science Based Health) is another formulation with some of the same nutrients as above, including: ginkgo biloba extract, coenzyme Q10, bilberry fruit extract, n-acetylsteine, alpha lipoic acid, grape seed extract, taurine, quercetin, omega-3 fatty acids, vitamins C/E/B6/B12, folate and magnesium. A randomized controlled double-masked crossover study reported increase in biomarkers of ocular blood flow within retinal and retrobulbar vasculature after 1 month of consumption.⁷

HOW SHOULD I ADDRESS EXPECTATIONS?

It is important to discuss patient expectations of these nutritional supplements with your patients in advance. Common questions include:

• Can supplements reverse functional damage? Patients should understand that they might not notice any subjective improvement in vision. Reversal of functional damage has been reported in the literature (mostly by electrophysiological testing), but this may not relate to subjective change. Research focusing on answering this question using contrast sensitivity and more intense visual field testing is ongoing.
• Can supplements slow progression? This may be especially important in patients who have shown rapid progression despite adequate IOP-lowering treatment, but we don’t have adequate studies to answer yet.
• Can supplements prevent damage? This may be applicable to glaucoma suspects and patients with a family history of glaucoma and is also not yet proven, although animal models seem to offer hope.
• What is a supplement’s duration of action? The supplement may have to be taken for 2 to 3 months prior to achieving an effect. Additionally, the limited studies we have suggest there may be partial effect regression after supplement washout. Therefore, it is important for the patient to find a supplement that they can tolerate and afford in the long term.

WHAT ARE THE PRACTICAL CONSIDERATIONS?

When recommending nutritional supplements at my practice, I discuss a few matters with patients:

• Quality control of nutritional supplements can be variable. I recommend that patients obtain nutritional supplements from reliable sources, ideally with a good manufacturing practice (GMP) certification or manufacturers who have passed certain quality criteria from organizations such as Consumer Lab (consumerlab.com ).
• Caution patients regarding dosages, as these are not well studied. The Table lists dosages used during RCTs, but these may not reflect the ideal dose for every patient. If taking multiple supplements, it may be safer to lean towards lower doses.
• Recommend the patient discuss the supplements with their primary-care doctor and relevant subspecialists. This can help avoid unintended interactions with current medications or other contraindications.
• Encourage diet modifications as well. This includes eating a well-balanced diet, antioxidant-rich foods, dietary nitrates, green leafy vegetables and moderation of caffeine.
• Safety is paramount. Safety data is difficult to gather from smaller sample size studies limited to ophthalmology, but many of these substances have been used in larger trials in the setting of other neurodegenerative diseases and systemic conditions. Overall, if the physician is aware of contraindicated conditions and other providers are aware of the supplement use (so as to avoid/minimize any potential interaction with other medications), there should be low risk of serious adverse events. As an example, the Table lists some safety considerations for the selected nutrients.

SHOULD I BE HESITANT?

A survey of Canadian ophthalmologists found that less than a quarter (22%) felt that CAM has a role in glaucoma therapy.⁸ I understand the hesitance of many ophthalmologists in recommending nutritional supplements, as it often centers on a lack of convincing data. However, it is important to understand why more substantial research is not available at this time:

• Nutritional supplement studies have a smaller sample size compared to traditional pharmaceutical trials. This relates to limited funding and the fact that supplements do not require approval from the FDA. With limited funding and sample size, it is difficult to determine which patients to enroll and which will benefit the most amongst our spectrum of glaucoma patients.
• Promising animal model data may not translate to human studies. An animal model utilized for a specific study is homogenous whereas clinical glaucoma in patients is heterogenous. Also, animal studies often administer neuroprotective agents at the time of, or before, the injury. On the other hand, neuroprotective agents are often administered long after damage has begun in patients. In addition, study endpoints in animal studies are often structural, whereas they tend to be functional in human studies. Finally, human metabolism and ocular bioavailability are difficult to predict and measure despite what may have been predicted from animal studies.

CONCLUSION

Nutritional supplements may have a role as complimentary therapy to IOP lowering in glaucoma; their utility will hopefully be further clarified by larger, well-designed clinical trials in the future. It is important to familiarize ourselves with options that may be more appropriate or promising for patients who are interested in complimentary therapies, as long as safety remains a priority and their conventional care is not compromised. Hopefully, this article has tackled a few of the practical barriers we face in understanding the clinical role of nutritional supplementation in glaucoma. OM

REFERENCES

1. Wan MJ, Daniel S, Kassam F, et al. Survey of complementary and alternative medicine use in glaucoma patients. J Glaucoma. 2012;21:79-82.
2. Morrone LA, Rombola L, Adornetto A, et al. Rational Basis for Nutraceuticals in the Treatment of Glaucoma. Curr Neuropharmacol. 2018;16:1004-1017.
3. Nucci C, Martucci A, Giannini C, et al. Neuroprotective agents in the management of glaucoma. Eye (Lond). 2018;32:938-945.
4. Saccà SC, Corazza P, Gandolfi S, et al. Substances of Interest That Support Glaucoma Therapy. Nutrients. 2019;11:239.
5. Loskutova E, O’Brien C, Loskutov I, Loughman J. Nutritional supplementation in the treatment of glaucoma: A systematic review. Surv Ophthalmol. 2019;64:195-216.
6. Ritch R, Suwan Y, Rosen R, De Moraes CG. Randomized Double-Masked Placebo-Controlled Trial of the Efficacy of a Novel Neuroprotective Combination for Reversing Mitochondrial Dysfunction in Glaucoma. Poster Presentation at American Glaucoma Society Annual Meeting 2018.
7. Harris A, Gross J, Moore N, et al. The effects of antioxidants on ocular blood flow in patients with glaucoma. Acta Ophthalmol. 2018;96:e237-e241.
8. Bower TN, Muhsen S, Overbury O, Birt C, Kasner O. Canadian ophthalmologists’ opinions concerning complementary and alternative medicine (CAM) use in glaucoma. J Glaucoma. 2014;23:430-434.

About the Author

Natasha Nayak Kolomeyer, MD, is a glaucoma specialist and assistant professor of ophthalmology at Wills Eye Hospital in Philadelphia, Pa.

Dr. Kolomeyer disclosed financial relationships with Aerie, Allergan, Diopsys, Equinox, Glaukos, Guardion Health Services, Nicox, Olleyes and Santen.