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HomemieyecareIs it Time to Talk? Nutraceutical Supplements and Glaucoma

Is it Time to Talk? Nutraceutical Supplements and Glaucoma

With the burden of glaucoma in Australia rising, is it time to start a conversation with patients about the role of supplements in glaucoma management? Drs Varun Chandra and Brian Ang review the evidence.

Glaucoma affects an estimated 6.9 million people worldwide and is one of the leading causes of irreversible blindness.1 In Australia, glaucoma affects almost 200,000 non- Indigenous Australians over age 50 and more than 2,000 Indigenous Australians over age 40.2

The traditional principles of medical and surgical glaucoma management are targeted at lowering intraocular pressure (IOP) as the most readily modifiable risk factor. However, in some patients with adequate IOP control, the continued progression of glaucomatous optic neuropathy suggests the aetiology is not just IOP-related, but likely to be multifactorial.1 The pathogenesis of glaucoma has thus been proposed as a complex interplay of oxidative stress, mitochondrial dysfunction, as well as mechanical, vascular, neuroinflammatory and genetic factors.1

There is a growing body of literature supporting the potential role of nutraceutical supplements as an adjunct to traditional IOP lowering therapies. This article re-examines the evidence in glaucoma management for ginkgo biloba and nicotinamide, and we also touch on the issue of proactively discussing supplements for neuroprotection with patients.

GINKGO BILOBA

Ginkgo biloba extract (GBE) is derived from the leaves of the ginkgo tree, which is native to China, Japan and Korea.3

Standardised GBE, such as EGb761, contains numerous novel phytochemicals including ginkgolides (3.1%), bilobalides (2.9%), and flavonoids (24%).4 These phytochemicals act as potent antioxidants at the mitochondrial level, unlike general antioxidants such as vitamin C. This helps with stabilising the inner mitochondrial membrane and assists with adenosine triphosphate (ATP) production.4,5

Other described effects include reducing blood viscosity and inhibiting platelet aggregation by increasing concentrations of thrombolytics such as nitrous oxide,5 and modulation of neurotransmitter disturbances.3

The potential beneficial effects of GBE for glaucoma have been fairly well documented. Improvements in ocular blood flow have been demonstrated in the retinal capillaries, peripapillary region, retrobulbar blood vessels, and ophthalmic artery.6-8

The most compelling evidence for the role of GBE in normal tension glaucoma (NTG) comes from a well-designed randomised cross-over trial by Quaranta et al. in a cohort of NTG patients in Italy, which analysed the effect of 40mg three times daily on visual fields.3 After four weeks of GBE treatment, there was a significant improvement in Humphrey visual field (HVF) test indices, including mean deviation (MD) and corrected pattern standard deviation (PSD). Notably, a regression in visual field indices was evident after cessation of GBE, suggesting a limited duration of action and need for ongoing therapy.

Interestingly, a similarly designed trial to Quaranta et al. in a Chinese cohort with identical GBE dosing, did not detect significant improvement of visual field or contrast sensitivity.9

The potential beneficial effects of GBE for glaucoma have been fairly well documented

Further supporting evidence for the neuroprotective effects of GBE in NTG are two independent retrospective reviews originating from Korea. These studies evaluated NTG patients receiving GBE 160mg per day.10,11 Shim et al. reported a significant improvement in MD after 24 months mean duration of treatment.10 Lee et al. had a longer follow-up period of at least four years and reported significant improvement in progression rates of MD and PSD.11 No adverse events related to GBE were reported in any of the referenced studies.3, 9-11 Nevertheless, the vasomodulatory properties of GBE have raised potentially overstated concerns about the increased risk of bleeding.12 However, the association between bleeding risk and GBE is predominantly based on case reports (i.e. Level 4 evidence).13 Higher level evidence has not shown a significant bleeding risk with GBE supplementation. A randomised control trial (RCT) showed no effect of GBE on 29 separate blood coagulation and platelet aggregation parameters.14 A large metaanalysis of 18 RCTs reported that despite a significant reduction in blood viscosity, there was no significant effect on platelet aggregation, fibrinogen concentration, or prothrombin levels.15 The authors concluded standardised GBE does not increase bleeding risk, but this cannot be extrapolated to nonstandardised extracts, herbal teas, or crude leaf preparations. A separate review has also found that GBE does not interact with other anticoagulative or antiplatelet medications.16

Ginkgo biloba and nicotinamide are but two of a growing number of nutraceutical supplements that have shown significant promise in human clinical trials as a potential adjunct for glaucoma management

NICOTINAMIDE

The nicotinamide form of vitamin B3 is another vitamin that has received great interest for glaucoma neuroprotection. This stems from research strongly associating mitochondrial dysfunction within retinal ganglion cells (RGCs) with the pathogenesis of glaucoma.17,18 It has also been observed that increasing nicotinamide adenine dinucleotide (NAD) levels (which naturally decline with age) through nicotinamide supplementation can reduce RGC mitochondria susceptibility during periods of elevated IOP.18

For glaucoma neuroprotection, direct supplementation with nicotinamide is preferred to other NAD precursors. Nicotinic acid and niacin are unsuitable due to significant adverse effects. Unlike nicotinamide, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are unable to cross the blood-brain barrier, and thus cannot directly increase NAD levels in RGCs. Both NMN and NR are converted to nicotinamide in the liver, and nicotinamide alone is thought to maintain systemic NAD homeostasis.19

The effects of high-dose nicotinamide in glaucoma have been reported in two short trials. The first was a crossover randomised clinical trial that examined the effect of oral nicotinamide supplementation on inner retinal function in glaucoma patients.17 Participants received six weeks of 1.5g/day, then six weeks of 3g/day then crossover to placebo or vice versa. The authors reported an improvement on inner retinal function in glaucoma patients with nicotinamide supplementation at a daily dose of 3g.

The second was a randomised clinical trial of mild to moderate open-angle glaucoma patients who were supplemented with both nicotinamide and pyruvate in increasing doses. Over a median follow-up of 2.2 months, the authors reported a significantly higher number of improving visual field test locations and PSD improvement, although there was no significant improvement in MD.20

A major limitation of these two studies is the short follow-up period. Although both trials reported no major adverse events with high dose nicotinamide, the long-term tolerability and side effects are still unclear. Two prospective studies are now underway to examine this very issue of long-term effects of nicotinamide for glaucoma patients (Clinical Trials ID NCT05275738, NCT 05405868).21

DISCUSSION

Ginkgo biloba and nicotinamide are but two of a growing number of nutraceutical supplements that have shown significant promise in human clinical trials as a potential adjunct for glaucoma management, particularly over the short to medium term.

The question as to whether clinicians should proactively discuss these complementary therapies with patients can be controversial.

Patients are already able to easily access abundant information about these complementary therapies via the internet

On one hand, to the best of our knowledge there is no high-level evidence of the long-term benefits for these nutraceutical supplements and the financial cost may be prohibitive for some.

On the other hand, the concept of consuming supplements for neuroprotection makes sense to most glaucoma patients, particularly those who are at higher risk of progression to glaucoma blindness. Patients desire autonomy in their medical treatment, and to know that they have done everything possible to reduce their risk of vision loss from glaucoma.22,23

Our personal opinion is that there is sufficient evidence to warrant open two-way discussion with patients. We do not necessarily have to wait for irrefutable long-term evidence to be published prior to discussion of potential neuroprotection options with patients.

Patients are already able to easily access abundant information about these complementary therapies via the internet. Furthermore, a survey of glaucoma patients reported that 10% already take some form of complementary and alternative medicine, and the majority (62%) do not disclose this to their ophthalmologist.24

Acting in the best interests of our patients should be at the core of our clinical practice. We believe this includes doing our best to educate our patients on nutraceutical supplements for neuroprotection and supporting them in their decision making based on their individual circumstances.

Glossary References

Adenosine triphosphate (ATP) – energy-carrying molecule found in the cells of all living things. ATP captures chemical energy obtained from the breakdown of food molecules and releases it to fuel other cellular processes.

Fibrinogen – a soluble protein present in blood plasma, from which fibrin for blood clotting is produced by the action of the enzyme thrombin.

Nicotinamide adenine dinucleotide (NAD) – a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other nicotinamide.

Nutraceuticals – a term derived from “nutrition” and “pharmaceuticals”. It is applied to ingredients and extracts that are isolated from herbal products and dietary supplements and used for their medicinal properties.1

Phytochemicals – chemicals produced by plants. The term is generally used to describe chemicals from plants that may affect health but are not essential nutrients. Examples include carotenoids and flavonoids.2

Prothrombin – a protein produced by the liver. It is one of many factors in blood that help it to clot appropriately.3

Pyruvate – an important molecule that is present at the intersection of multiple biochemical pathways. It is one of the end products of glycolysis, which is then transported to the mitochondria for participation in the citric acid cycle. In the absence of oxygen, pyruvate can undergo fermentation to produce lactate. Pyruvate can also be involved in the anabolic synthesis of fatty acids and amino acids.4

Thrombolytics – thrombolytics (fibrinolytic drugs) are “clot-busting” drugs that break up and dissolve blood clots that get in the way of blood flow. Fibrinolytics are enzymes that kick off the process of breaking down proteins (fibrin) that form clots.5

References

  1. Kalra E.K., Nutraceutical – Definition and introduction. AAPS Pharm Sci. 2003;5:E25.
  2. lpi.oregonstate.edu/mic/dietary-factors/phytochemicals.
  3. www.mayoclinic.org/tests-procedures/prothrombin-time/about/pac-20384661.
  4. biologydictionary.net/pyruvate/
  5. my.clevelandclinic.org/health/treatments/23238-thrombolytics.

The opinions expressed in this article are the authors’ own, and do not reflect hospital and practice policy.

Dr Varun Chandra is a senior ophthalmology registrar based at the Royal Victorian Eye and Ear Hospital in Melbourne. Prior to commencing ophthalmology training in Victoria, Dr Chandra completed his medical degree at the University of New South Wales, graduating with MBBS (Honours). He was the recipient of the Adam Locket Memorial Award for Ophthalmic Anatomy from the University of Sydney in 2015.

Dr Brian Ang is a glaucoma specialist and researcher based at the Royal Victorian Eye and Ear Hospital and Centre for Eye Research Australia respectively. He has over 70 peer reviewed publications, with research interests in novel surgical treatments and neuroprotection for glaucoma. Dr Ang is a keen advocate of ‘proactive glaucoma’ – the proactive management of risk for glaucoma and glaucoma suspect patients.

References

  1. Sim R.H., Sirasanagandla S.R., Das S., Teoh S.L., Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update. Nutrients. 2022;14(3):534.
  2. Keel S., Xie J., Foreman J., et al., Prevalence of glaucoma in the Australian national eye health survey. Br J Ophthalmol. 2019;103(2):191–5.
  3. Quaranta L., Bettelli S., Uva M.G., Semeraro F., Turano R., Gandolfo E., Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Ophthalmology. 2003;110(2):359–62.
  4. Isah T., Rethinking Ginkgo biloba L.: Medicinal uses and conservation. Pharmacogn Rev. 2015;9(18):140.
  5. Diamond B.J., Shiflett S.C., Feiwel N., et al., Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil. 2000;81(5):668–78.
  6. Park J.W., Kwon H.J., Chung W.S., Kim C.Y., Seong G.J., Short-term effects of Ginkgo biloba extract on peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol. 2011;25(5):323–8.
  7. Harris A., Gross J., Moore N., et al., The effects of antioxidants on ocular blood flow in patients with glaucoma. Acta Ophthalmol (Copenh). 2018;96(2):e237–41.
  8. Chung H.S., Harris A., Kristinsson J.K., et al., Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther. 1999;15(3):233–40.
  9. Guo X., Kong X., Huang R., et al., Effect of Ginkgo biloba on visual field and contrast sensitivity in Chinese patients with normal tension glaucoma: a randomized, crossover clinical trial. Invest Ophthalmol Vis Sci. 2014;55(1):110–6.
  10. Shim S.H., Kim J.M., Choi C.Y., et al., Ginkgo biloba extract and bilberry anthocyanins improve visual function in patients with normal tension glaucoma. J Med Food. 2012;15(9):818–23.
  11. Lee J., Sohn S.W., Kee C., Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma. J Glaucoma. 2013;22(9):780–4.
  12. Ahmad S.S., Bilal S.M., Tariq A., Rashid A. Dietary Intervention in Glaucoma. TouchREVIEWS Ophthalmol. 2022.
  13. Bent S., Goldberg H., Padula A., Avins A.L., Spontaneous bleeding associated with Ginkgo biloba: a case report and systematic review of the literature. J Gen Intern Med. 2005;20(7):657–61.
  14. Köhler S., Funk P., Kieser M., Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebocontrolled, double-blind study in healthy volunteers. Blood Coagul Fibrinolysis. 2004;15(4):303–9.
  15. Kellermann A.J., Kloft C., Is There a Risk of Bleeding Associated with Standardized Ginkgo biloba Extract Therapy? A Systematic Review and Metaanalysis. Pharmacother J Hum Pharmacol Drug Ther. 2011;31(5):490–502.
  16. Labkovich M., Jacobs E.B., Bhargava S., et al., Ginkgo Biloba extract in ophthalmic and systemic disease, with a focus on normal-tension glaucoma. Asia-Pac J Ophthalmol Phila Pa. 2020;9(3):215.
  17. Hui F., Tang J., Williams P.A., et al., Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial. Clin Experiment Ophthalmol. 2020;48(7):903–14.
  18. Williams P.A., Harder J.M., John S.W., Glaucoma as a metabolic optic neuropathy: making the case for nicotinamide treatment in glaucoma. J Glaucoma. 2017;26(12):1161.
  19. Tribble J.R., Hui F., Jöe M., et al., Targeting diet and exercise for neuroprotection and neurorecovery in glaucoma. Cells. 2021;10(2):295.
  20. De Moraes C.G., John S.W., Williams P.A., Blumberg D.M., et al., Nicotinamide and pyruvate for neuroenhancement in open-angle glaucoma: a phase 2 randomized clinical trial. JAMA Ophthalmol. 2022;140(1):11–8.
  21. Kuo C.Y., Liu C.J.L., Neuroprotection in Glaucoma: Basic Aspects and Clinical Relevance. J Pers Med. 2022;12(11):1884.
  22. Gatwood J., Brooks C., Meacham R., et al., Facilitators and Barriers to Glaucoma Medication Adherence. J Glaucoma. 2022;31(1):31–6.
  23. Lu T.C., Semsarian C.R., White A., et al., Journey to glaucoma care–trusting but uncertain and uninformed: a qualitative study. Clin Exp Optom. 2020;103(4):484–9.
  24. Wan M.J., Daniel S., Kassam F., et al. Survey of complementary and alternative medicine use in glaucoma patients. J Glaucoma. 2012;21(2):79–82.