While intraocular pressure (IOP) lowering therapy can slow or halt glaucoma, some patients continue to lose vision despite adequate IOP reduction. Thus, neuroprotective agents that slow retinal ganglion cell damage independent of IOP reduction are needed.To address this unmet need, Aakriti Garg Shukla, M.D., MSc, and Jeffrey Liebmann, M.D., ophthalmologists at in the Glaucoma Division at NewYork-Presbyterian and Columbia, are investigating the neuroprotective effects of nicotinamide and pyruvate.
Below, Dr. Shukla discusses her ongoing research looking for ways to slow the progression of glaucoma and her involvement in developing a joint position statement for the American Glaucoma Society and the American Academy of Ophthalmology on nicotinamide.
Nicotinamide is a promising candidate for glaucoma neuroprotection, as it has been shown to improve mitochondrial health in glaucoma and other conditions.
— Dr. Aakriti Shukla
Studying the Use of Nicotinamide and Pyruvate
Simon John, Ph.D., a basic scientist at Columbia, discovered that metabolic and mitochondrial dysfunction occurred in retinal ganglion cells before detectable optic nerve damage. Nicotinamide is a promising candidate for glaucoma neuroprotection, as it has been shown to improve mitochondrial health in glaucoma and other conditions. Additionally, low retinal pyruvate levels are associated with dysregulated glucose metabolism in mouse models of glaucoma. Laboratory studies have found that oral supplementation with nicotinamide and pyruvate was more effective than either agent alone at preventing glaucomatous neurodegeneration.
Results from a phase 2 study demonstrated that nicotinamide and pyruvate can help improve the visual field in patients with glaucoma.
Based on these findings, members of the Glaucoma Division conducted a phase 2, eight-week pilot study to assess the efficacy of nicotinamide and pyruvate for treating glaucoma. Our results demonstrated that patients randomized to receive both nicotinamide and pyruvate showed an improvement in their visual field compared to patients randomized to placebo.
While clinical trials investigating nicotinamide are taking place worldwide, NewYork-Presbyterian and Columbia is the only site in the United States to have initiated a trial examining nicotinamide and pyruvate, and I am the principal investigator for the trial. Led by study chair Dr. Liebmann, an ophthalmologist and director of the Glaucoma Division at NewYork-Presbyterian and Columbia, we are enrolling patients in a phase 3, multicenter, randomized controlled trial assessing nicotinamide and pyruvate as potential neuroprotective treatments for glaucoma. In this trial, patients are randomized to receive either nicotinamide and pyruvate or placebo. These patients will be followed for a period of 21 months from the study's initiation with close monitoring of the structure and function of their optic nerves. Our goal is to recruit approximately 200 patients for the trial. Our last patient will be enrolled this year, and we expect to see results in late 2027.
Position Statement on Nicotinamide Use for Glaucoma Neuroprotection
As a member of the American Glaucoma Society, I was asked to write a position statement for the organization on the use of nicotinamide for glaucoma neuroprotection. The need for this position statement arose from patients’ and physicians’ interest in nicotinamide as a potential way to treat glaucoma. Since nicotinamide is an over-the-counter nutraceutical that is readily available and is not regulated, patients may be using this supplement without full awareness of its potential risks. Providing guidance on the use of nicotinamide was important, as there have been two cases of clinical trial participants who have experienced drug-induced liver injury. One case was in our trial, and another was in a trial in Singapore. Fortunately, they were both diagnosed early enough to receive appropriate treatment, their drug-induced liver injury was reversed, and they are doing well with no lasting effects.
Our trials demonstrate that there are some potentially deleterious outcomes that can happen with the use of over-the-counter supplement nicotinamide. Given the buzz surrounding nicotinamide in glaucoma and other conditions, we thought it was important to get the word out about these potential adverse outcomes.
Our trials demonstrate that there are some potentially deleterious outcomes that can happen with the use of over-the-counter supplement nicotinamide.
— Dr. Aakriti Garg Shukla
The position statement, which was published by both the American Glaucoma Society and the American Academy of Ophthalmology, highlights several key points about nicotinamide use:
- While nicotinamide is a potentially promising treatment for glaucoma, it has not been approved by the FDA and therefore, its overall safety is unknown.
- We do not recommend using clinical trial doses (equal to or greater than 3 grams/day) of nicotinamide outside of the clinical trial setting that involves close monitoring of liver function.
- If you're considering using lower doses, it's important to involve your internist and to monitor liver function closely.
Additionally, patients should be informed about the possible side effects of nicotinamide and of the presentation of drug-induced liver injury, which can include nausea, vomiting, and yellowing of the eyes and skin. If a patient observes any of these findings, they need to report them immediately to their internist or go to the emergency room, depending on the severity of symptoms. If the patient is enrolled in a clinical trial, these symptoms should also be reported to the FDA via the FDA safety reporting portal.
Any patient who has a current or prior history of liver dysfunction should not be offered nicotinamide as a potential therapy for glaucoma or any other condition. Very importantly, while niacin is a form of vitamin B3 and nicotinamide is the amide derivative of niacin, niacin and nicotinamide are not interchangeable. Niacin, which has not shown any benefit in glaucoma and can be hepatotoxic at high doses, should not be taken in place of nicotinamide.
We are optimistic that nicotinamide can play a role in preserving the optic nerve and visual function and preventing our patients from losing vision. However, we need to be cautious with its use and ensure that these patients know about the potential risks and are monitored closely.
