Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial | Glaucoma | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle GlaucomaA Phase 2 Randomized Clinical Trial

Educational Objective
To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.
1 Credit CME
Key Points

Question  Does a combination of oral nicotinamide and pyruvate help with short-term improvement in visual function in individuals with glaucoma?

Findings  In this phase 2, randomized clinical trial, a combination of nicotinamide and pyruvate was safe and the number of improving visual field test locations was higher in the treatment group vs the placebo group over a median of 2.2 months.

Meaning  Oral nicotinamide and pyruvate can result in short-term improvement in visual function in patients with treated, manifest glaucoma.

Abstract

Importance  Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting.

Objective  To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.

Design, Setting, and Participants  In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021.

Interventions  Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization).

Main Outcomes and Measures  Number of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]).

Results  Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6-25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, −0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs −0.002 dB per week; 95% CI, −0.27 to 0.09; P = .35) or VFI (0.09 vs −0.02% per week; 95% CI, −0.53 to 0.36; P = .71).

Conclusions and Relevance  A combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

Trial Registration  ClinicalTrials.gov Identifier: NCT03797469

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 13, 2021.

Published Online: November 18, 2021. doi:10.1001/jamaophthalmol.2021.4576

Corresponding Author: Carlos Gustavo De Moraes, MD, MPH, PhD, Columbia University Irving Medical Center, 635 W 165th St, Box 69, New York, NY 10032 (cvd2109@cumc.columbia.edu).

Author Contributions: Drs De Moraes and Liebmann had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: De Moraes, John, Williams, Cioffi, Liebmann.

Acquisition, analysis, or interpretation of data: De Moraes, John, Blumberg, Cioffi, Liebmann.

Drafting of the manuscript: De Moraes, Cioffi, Liebmann.

Critical revision of the manuscript for important intellectual content: De Moraes, John, Williams, Blumberg, Cioffi, Liebmann.

Statistical analysis: De Moraes.

Obtained funding: Cioffi.

Administrative, technical, or material support: Blumberg, Cioffi, Liebmann.

Supervision: De Moraes, Williams, Cioffi, Liebmann.

Conflict of Interest Disclosures: Dr De Moraes reports support from Allergan, Belite, Carl Zeiss Meditec, Galimedix, Genentech, Novartis, Ora, Thea, and Reichert outside the submitted work and from Heidelberg Engineering, the National Institutes of Health, the US Centers for Disease Control and Prevention, and Topcon during the conduct of the study. Drs John and Williams are inventors on a patent application filed by the Jackson Laboratory that covers nicotinamide- and pyruvate-based therapies in glaucoma. Dr John was employed by Howard Hughes Medical Institute during the conduct of the study. Dr Liebmann reports support from Allergan, Carl Zeiss Meditec, Genentech, and Thea outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the Shirlee and Bernard Brown Glaucoma Genetics Initiative at the Department of Ophthalmology, Columbia University Irving Medical Center and by Research to Prevent Blindness. Dr John was an investigator of Howard Hughes Medical Institute and supported by funds from the Precision Medicine Initiative at Columbia University. Dr Williams is supported by Karolinska Institutet in the form of a board of research faculty–funded career position and by philanthropic donations from the St Erik Eye Hospital (Vetenskapsrådet 2018-02124).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

References
1.
Gordon  MO , Beiser  JA , Brandt  JD ,  et al.  The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma.   Arch Ophthalmol. 2002;120(6):714-720. doi:10.1001/archopht.120.6.714PubMedGoogle ScholarCrossref
2.
Leske  MC , Heijl  A , Hussein  M , Bengtsson  B , Hyman  L , Komaroff  E ; Early Manifest Glaucoma Trial Group.  Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.   Arch Ophthalmol. 2003;121(1):48-56. doi:10.1001/archopht.121.1.48PubMedGoogle ScholarCrossref
3.
The AGIS Investigators.  The Advanced Glaucoma Intervention Study (AGIS): 7. the relationship between control of intraocular pressure and visual field deterioration.   Am J Ophthalmol. 2000;130(4):429-440. doi:10.1016/S0002-9394(00)00538-9PubMedGoogle ScholarCrossref
4.
Collaborative Normal-Tension Glaucoma Study Group.  The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma.   Am J Ophthalmol. 1998;126(4):498-505. doi:10.1016/S0002-9394(98)00272-4PubMedGoogle ScholarCrossref
5.
Garway-Heath  DF , Crabb  DP , Bunce  C ,  et al.  Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.   Lancet. 2015;385(9975):1295-1304. doi:10.1016/S0140-6736(14)62111-5PubMedGoogle ScholarCrossref
6.
Krupin  T , Liebmann  JM , Greenfield  DS , Ritch  R , Gardiner  S ; Low-Pressure Glaucoma Study Group.  A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study.   Am J Ophthalmol. 2011;151(4):671-681. doi:10.1016/j.ajo.2010.09.026PubMedGoogle ScholarCrossref
7.
Susanna  R  Jr , De Moraes  CG , Cioffi  GA , Ritch  R .  Why do people (still) go blind from glaucoma?   Transl Vis Sci Technol. 2015;4(2):1. doi:10.1167/tvst.4.2.1PubMedGoogle ScholarCrossref
8.
Furlanetto  RL , De Moraes  CG , Teng  CC ,  et al; Low-Pressure Glaucoma Treatment Study Group.  Risk factors for optic disc hemorrhage in the low-pressure glaucoma treatment study.   Am J Ophthalmol. 2014;157(5):945-952. doi:10.1016/j.ajo.2014.02.009PubMedGoogle ScholarCrossref
9.
Huynh  B , Shah  P , Sii  F , Hunter  D , Carnt  N , White  A .  Low systemic vitamin D as a potential risk factor in primary open-angle glaucoma: a review of current evidence.   Br J Ophthalmol. 2021;105(5):595-601. doi:10.1136/bjophthalmol-2020-316331PubMedGoogle ScholarCrossref
10.
Kouassi Nzoughet  J , Chao de la Barca  JM , Guehlouz  K ,  et al.  Nicotinamide deficiency in primary open-angle glaucoma.   Invest Ophthalmol Vis Sci. 2019;60(7):2509-2514. doi:10.1167/iovs.19-27099PubMedGoogle ScholarCrossref
11.
Marino  PF , Rossi  GCM , Campagna  G , Capobianco  D , Costagliola  C ; Qualicos Study Group.  Effects of citicoline, homotaurine, and vitamin E on contrast sensitivity and visual-related quality of life in patients with primary open-angle glaucoma: a preliminary study.   Molecules. 2020;25(23):E5614. doi:10.3390/molecules25235614PubMedGoogle Scholar
12.
Hui  F , Tang  J , Williams  PA ,  et al.  Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: a crossover randomized clinical trial.   Clin Exp Ophthalmol. 2020;48(7):903-914. doi:10.1111/ceo.13818PubMedGoogle ScholarCrossref
13.
Rolle  T , Dallorto  L , Rossatto  S , Curto  D , Nuzzi  R .  Assessing the performance of daily intake of a homotaurine, carnosine, forskolin, vitamin B2, vitamin B6, and magnesium based food supplement for the maintenance of visual function in patients with primary open angle glaucoma.   J Ophthalmol. 2020;2020:7879436. doi:10.1155/2020/7879436PubMedGoogle Scholar
14.
Tribble  JR , Vasalauskaite  A , Redmond  T ,  et al.  Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma.   Brain Commun. 2019;1(1):fcz035. doi:10.1093/braincomms/fcz035PubMedGoogle Scholar
15.
Williams  PA , Harder  JM , Foxworth  NE ,  et al.  Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.   Science. 2017;355(6326):756-760. doi:10.1126/science.aal0092PubMedGoogle ScholarCrossref
16.
Tribble  JR , Otmani  A , Sun  S ,  et al.  Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.   Redox Biol. 2021;43:101988. doi:10.1016/j.redox.2021.101988PubMedGoogle Scholar
17.
Gomes  AP , Price  NL , Ling  AJ ,  et al.  Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.   Cell. 2013;155(7):1624-1638. doi:10.1016/j.cell.2013.11.037PubMedGoogle ScholarCrossref
18.
Williams  PA , Harder  JM , Foxworth  NE , Cardozo  BH , Cochran  KE , John  SWM .  Nicotinamide and WLDS act together to prevent neurodegeneration in glaucoma.   Front Neurosci. 2017;11:232. doi:10.3389/fnins.2017.00232PubMedGoogle ScholarCrossref
19.
Williams  PA , Harder  JM , Cardozo  BH , Foxworth  NE , John  SWM .  Nicotinamide treatment robustly protects from inherited mouse glaucoma.   Commun Integr Biol. 2018;11(1):e1356956. doi:10.1080/19420889.2017.1356956PubMedGoogle Scholar
20.
Harder  JM , Braine  CE , Williams  PA ,  et al.  Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective.   Proc Natl Acad Sci U S A. 2017;114(19):E3839-E3848. doi:10.1073/pnas.1608769114PubMedGoogle ScholarCrossref
21.
Williams  PA , Harder  JM , John  SWM .  Glaucoma as a metabolic optic neuropathy: making the case for nicotinamide treatment in glaucoma.   J Glaucoma. 2017;26(12):1161-1168. doi:10.1097/IJG.0000000000000767PubMedGoogle ScholarCrossref
22.
Harder  JM , Guymer  C , Wood  JPM ,  et al.  Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.   Proc Natl Acad Sci U S A. 2020;117(52):33619-33627. doi:10.1073/pnas.2014213117PubMedGoogle ScholarCrossref
23.
De Moraes  CG , Liebmann  JM , Levin  LA .  Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma.   Prog Retin Eye Res. 2017;56:107-147. doi:10.1016/j.preteyeres.2016.10.001PubMedGoogle ScholarCrossref
24.
Cordeiro  MF , Levin  LA .  Clinical evidence for neuroprotection in glaucoma.   Am J Ophthalmol. 2011;152(5):715-716. doi:10.1016/j.ajo.2011.06.015PubMedGoogle ScholarCrossref
25.
Lawlor  M , Danesh-Meyer  H , Levin  LA , Davagnanam  I , De Vita  E , Plant  GT .  Glaucoma and the brain: trans-synaptic degeneration, structural change, and implications for neuroprotection.   Surv Ophthalmol. 2018;63(3):296-306. doi:10.1016/j.survophthal.2017.09.010PubMedGoogle ScholarCrossref
26.
Crabb  DP , Garway-Heath  DF .  Intervals between visual field tests when monitoring the glaucomatous patient: wait-and-see approach.   Invest Ophthalmol Vis Sci. 2012;53(6):2770-2776. doi:10.1167/iovs.12-9476PubMedGoogle ScholarCrossref
27.
Bickler-Bluth  M , Trick  GL , Kolker  AE , Cooper  DG .  Assessing the utility of reliability indices for automated visual fields. testing ocular hypertensives.   Ophthalmology. 1989;96(5):616-619. doi:10.1016/S0161-6420(89)32840-5PubMedGoogle ScholarCrossref
28.
Yohannan  J , Wang  J , Brown  J ,  et al.  Evidence-based criteria for assessment of visual field reliability.   Ophthalmology. 2017;124(11):1612-1620. doi:10.1016/j.ophtha.2017.04.035PubMedGoogle ScholarCrossref
29.
Nair  AB , Jacob  S .  A simple practice guide for dose conversion between animals and human.   J Basic Clin Pharm. 2016;7(2):27-31. doi:10.4103/0976-0105.177703PubMedGoogle ScholarCrossref
30.
Knip  M , Douek  IF , Moore  WP ,  et al; European Nicotinamide Diabetes Intervention Trial Group.  Safety of high-dose nicotinamide: a review.   Diabetologia. 2000;43(11):1337-1345. doi:10.1007/s001250051536PubMedGoogle ScholarCrossref
31.
Jassim  AH , Coughlin  L , Harun-Or-Rashid  M , Kang  PT , Chen  YR , Inman  DM .  Higher reliance on glycolysis limits glycolytic responsiveness in degenerating glaucomatous optic nerve.   Mol Neurobiol. 2019;56(10):7097-7112. doi:10.1007/s12035-019-1576-4PubMedGoogle ScholarCrossref
32.
Wright  TM , Goharian  I , Gardiner  SK , Sehi  M , Greenfield  DS .  Short-term enhancement of visual field sensitivity in glaucomatous eyes following surgical intraocular pressure reduction.   Am J Ophthalmol. 2015;159(2):378-85.e1. doi:10.1016/j.ajo.2014.11.012PubMedGoogle ScholarCrossref
33.
Musch  DC , Gillespie  BW , Palmberg  PF , Spaeth  G , Niziol  LM , Lichter  PR .  Visual field improvement in the collaborative initial glaucoma treatment study.   Am J Ophthalmol. 2014;158(1):96-104.e2. doi:10.1016/j.ajo.2014.04.003PubMedGoogle ScholarCrossref
34.
Caprioli  J , de Leon  JM , Azarbod  P ,  et al.  Trabeculectomy can improve long-term visual function in glaucoma.   Ophthalmology. 2016;123(1):117-128. doi:10.1016/j.ophtha.2015.09.027PubMedGoogle ScholarCrossref
35.
Ahmed  OM , Waisbourd  M , Spaeth  GL , Katz  LJ .  Improvement in structure and visual function in patients with glaucoma: the possible key to better treatment?   Surv Ophthalmol. 2021;66(4):644-652. doi:10.1016/j.survophthal.2020.12.004PubMedGoogle ScholarCrossref
36.
Weber  AJ , Harman  CD .  Structure-function relations of parasol cells in the normal and glaucomatous primate retina.   Invest Ophthalmol Vis Sci. 2005;46(9):3197-3207. doi:10.1167/iovs.04-0834PubMedGoogle ScholarCrossref
37.
Fortune  B , Burgoyne  CF , Cull  GA , Reynaud  J , Wang  L .  Structural and functional abnormalities of retinal ganglion cells measured in vivo at the onset of optic nerve head surface change in experimental glaucoma.   Invest Ophthalmol Vis Sci. 2012;53(7):3939-3950. doi:10.1167/iovs.12-9979PubMedGoogle ScholarCrossref
38.
Yokota  S , Takihara  Y , Arimura  S ,  et al.  Altered transport velocity of axonal mitochondria in retinal ganglion cells after laser-induced axonal injury in vitro.   Invest Ophthalmol Vis Sci. 2015;56(13):8019-8025. doi:10.1167/iovs.15-17876PubMedGoogle ScholarCrossref
39.
Takihara  Y , Inatani  M , Eto  K ,  et al.  In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS.   Proc Natl Acad Sci U S A. 2015;112(33):10515-10520. doi:10.1073/pnas.1509879112PubMedGoogle ScholarCrossref
40.
Wu  Z , Medeiros  FA .  Impact of different visual field testing paradigms on sample size requirements for glaucoma clinical trials.   Sci Rep. 2018;8(1):4889. doi:10.1038/s41598-018-23220-wPubMedGoogle ScholarCrossref
41.
Wu  Z , Medeiros  FA .  Sample size requirements of glaucoma clinical trials when using combined optical coherence tomography and visual field endpoints.   Sci Rep. 2019;9(1):18886. doi:10.1038/s41598-019-55345-xPubMedGoogle ScholarCrossref
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close