Effect of treatment with sublingual vitamin B12 in patients with B12 deficiency

J Atherosclerosis Prev Treat. 2024 Jan-Apr;15(1):3-8 | doi:10.53590/japt.02.1056

RESEARCH ARTICLE

Georgia Anastasiou1, Fotios Barkas1, Ermioni Petkou1,  Stratos Alexiadis2, Efi Andalaki Foukaraki2, Angeliki Andreadou2, Vasilios Acholos2, Ignatios Giavazis2, Athanasios Garagounis2, Kyriaki Gratsia2, Ioanna Zografou2, Charalampos Kapernopoulos2, Fotios Karakostas2, Maria Kosmanou2, Konstantinos Kotsomytis2, Theoharis Koufakis2, Leonidas Kostalas2, Eleftheria Michalopoulou2, Loukas Balokas2, Maria Barbresou2, Eugenia Nikolaou2, Barbara Duska2, Dimitra Paraskeva2, Dimitris Skoutas2, Ioannis Spyrakopoulos2, Dimitrios Chrysis2, Maria Chorianopoulou2, Evangelos Liberopoulos3

1 Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina
2Private practice, 31st Propedeutic Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital of Athens


Abstract

Introduction: The efficacy of the intramuscular administration of vitamin B12 is well established, but it is limited by the fact that it should be administered by a healthcare professional and the associated local injection site reaction.

Aim: To investigate the effectiveness of sublingual vitamin B12 administration in patients with low serum B12 levels.

Patients and Methods: This is a retrospective study including patients with low serum levels of B12 (<200 pg/mL) and treated with 1000 μg/day sublingually (B12-SOLGAR®) for 3 months. Subjects’ main characteristics and personal history were recorded, as well as laboratory parameters before and 3 months after therapy initiation.

Results: 314 patients (men: 43%, age: 64 [54-75] years) were included in this study.  Most participants were on metformin (48%) and/or a proton pump inhibitor/H2 antagonist (50%). The administration of sublingual vitamin B12 was associated with a significant increase in serum B12 levels (from 182 [152-196] to 403 [312-590] pg/mL, p<0.05). Likewise, a significant increase was also noted in the patients with very low vitamin B12 levels (<100 pg/mL, n=21) (from 85 [74-92] pg/mL to 298 [294-340] pg/mL, p<0.05). Furthermore, significant improvements in hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cells, and platelets were observed.

Conclusions: The sublingual administration of vitamin B12 (1000 μg/day) for 3 months in patients with low B12 serum levels results in significant increases of B12 levels and improves hematologic parameters, and thus may be considered as an alternative to the intramuscular administration.

Key words: Vitamin B12 deficiency, sublingual administration, megaloblastic anemia

Corresponding author: Evangelos Liberopoulos MD, Professor of Medicine-Metabolic Diseases, 1st Propedeutic Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital of Athens, Ag. Thoma 17 str, Goudi, Athens, 11527, Tel.: +30 213 2061061, +30 6972022747, Fax: +30 213 2061794, E-mail: elibero@med.uoa.gr, vaglimp@yahoo.com

Submission: 11.12.2023, Acceptance: 09.04.2024


INTRODUCTION

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that is essential for the synthesis of DNA. B12 is derived from animal products, such as red meat, dairy, and eggs. Vitamin B12 absorption in the terminal ileum depends almost entirely on the intrinsic factor (IF), a glycoprotein secreted by parietal gastric cells.1 The recommended daily intake of vitamin B12 for adults ranges from 1 to 2 μg.2 A nutrient-rich diet typically supplies between 7 and 30 μg/day, whereas human liver can store B12 approximately 2-5 mg.3 Therefore, B12 deficiency may manifest 3-5 years after the diet no longer meets the necessary vitamin B12 requirements or absorption becomes insufficient. B12 deficiency is generally defined as serum B12 levels below 200 pg/mL (148 pmol/L), while levels ranging 200-300 pg/mL (148 to 221 pmol/L) are considered as borderline.4. In the latter case, additional testing of methylmalonic acid (MMA) and homocysteine levels is recommended;4-6 elevated MMA and homocysteine levels are indicative of B12 deficiency.4 Main causes of B12 deficiency include bariatric surgeries, prolonged use of metformin or proton pump inhibitors and histamine receptor 2 (H2) blockers, as well as malnutrition, strict vegetarianism  and autoimmune gastritis.1 B12 deficiency is more frequent in individuals older than 60 years.5 Currently, the exact prevalence of B12 deficiency globally is unknown.7,8 Vitamin B12 deficiency is a common cause of megaloblastic anemia, various neurological alterations owed to the progressive demineralization of the nervous system (a consequence of defective myelin synthesis), and psychiatric disturbances.1

The conventional treatment of vitamin B12 deficiency involves intramuscular (IM) administration of cyanocobalamin.9 Although IM administration is highly effective, it should be administered by a healthcare professional and is associated with bothersome local injection site reactions, such as pain.10 In this regard, oral and sublingual routes of B12 administration are gaining acceptance as alternative treatment to B12 deficiency.10,11 Of note, a recent large, retrospective study demonstrated superior efficacy of sublingual to IM administration.12

The aim of this study was to investigate the effectiveness of vitamin B12 sublingual administration (1000 μg/day) for at least 3 months in patients with low vitamin B12 serum levels.

PATIENTS AND METHODS

Study design and participants

This is a multicenter, retrospective study conducted in Greece and including adults (>18 years old) with B12 deficiency who were treated with sublingual vitamin B12 (B12-SOLGAR®) 1000 μg/day for 3 months. Patients with neurological symptoms, known allergies to cobalamin or to cobalt, Leber’s disease, polycythemia vera or hypokalemia, active malignancy, abnormalities of liver function, pregnancy, and patients on incompatible with vitamin B12 drugs (warfarin and phenothiazines) were excluded.  The study protocol was approved by the local institutional ethics committee and informed consent was obtained from each patient.

Subjects’ baseline characteristics, personal medical history and factors predisposing to vitamin B12 deficiency, as well as laboratory values were recorded at baseline visit (pre-treatment) and 3 months after sublingual vitamin B12 administration (post-treatment).

B12 deficiency was diagnosed in case of serum B12 levels ≤ below 200 pg/mL (<148 pmol/L). All B12 serum measurements were performed in International Organization for Standardization (ISO) certified laboratories. Drug compliance was monitored with patient-self reporting, interviews by healthcare providers and checking of remaining tablets in products’ packs.

Statistical analysis

Continuous variables were tested for normality by the Kolmogorov-Smirnov test and logarithmic transformations were performed if necessary. Data are presented as mean ± standard deviation (SD) and median (interquartile range [IQR]) for parametric and non-parametric data, respectively. For categorical values, frequency counts and percentages were applied. Chi-square test was performed for interactions between categorical values. Paired sample t-test (parametric and non-parametric) was used for the comparison of continuous numeric values pre- and post-treatment. Two-tailed significance was defined as p<0.05. Analyses were performed with the Statistical Package for Social Sciences (SPSS) v21.0 software (SPSS IBM Corporation, Armonk, New York, USA).

RESULTS

314 subjects (43% men, age: 64 [54-75] years) participated in the present study. Most patients were on metformin (47.5%) and/or a proton pump inhibitor/H2 antagonist (50.2%), while 15.3% were vegetarians or vegans (Table 1).

The sublingual administration of vitamin B12 was associated with a significant increase in serum B12 levels (from 182 [152-196] pg/mL to 403 [312-590)] pg/mL, p<0.05) (Table 2). Significant increases were also noted in hematocrit, white blood cells and platelets (p<0.05) (Table 2). Furthermore, mean corpuscular volume (MCV) decreased by 3.1% (from 96 [90-99] to 93 [88-96] fl, p< 0.05) (Table 2). Of note, percentage changes in vitamin B12 levels between participants on metformin and those not on metformin were not significantly different (p> 0.05).

In the subset of patients with very low B12 levels (<100 pg/mL, n=21) a significant increase in serum B12 was also noted (from 88 [76-92] pg/mL to 297 [254-386] pg/mL, p<0.05) (Table 3). Significant elevations were also observed in hematocrit, white blood cells and platelets (p<0.05) along with significant reduction in MCV [from 105 (102-112) to 90 (88-95) fl, p< 0.05] (Table 3).

All subjects persisted to the treatment during their follow-up and their adherence remained good (95%).

DISCUSSION

The present study shows that sublingual administration of vitamin B12 (1000 μg/day) for 3 months was associated with substantial increases in serum B12 levels and related hematological parameters in patients with low serum B12 levels, as well as those with very low baseline levels.

Our results are in line with previously published evidence. A small prospective study of 18 patients with vitamin B12 deficiency of various causes showed that sublingual administration of vitamin B12 (2 mg/day) for 7-12 days resulted in a significant increase of serum B12 levels by 302%.13 A 12-week randomized control trial of 40 vegans or vegetarian subjects with borderline vitamin B12 deficiency (<298 pg/mL) showed that sublingual low dose of 350 μg/week over 12 weeks was sufficient at restoring serum B12 levels compared with sublingual high dose of 2000μg/week.14 In a retrospective comparative study of 129 children with vitamin B12 deficiency (126 with inadequate dietary intake and 3 with pernicious anemia) aged 5-18 years, treatment with sublingual vitamin B12 1000 μg/day for 7 days and afterwards every other day for 3 weeks was as effective as the same dose pattern of IM administration of vitamin B12 in normalizing serum B12 levels.15 Similarly, in a retrospective study of 158 children aged 0-3 years with vitamin B12 levels <300 pg/mL who were treated with oral or sublingual or IM vitamin B12 (ratio 1:1:1), mean vitamin B12 levels increased to above 300 pg/mL  in all treatment groups (all p<0.05).16 A small study of 30 subjects with a serum B12 concentration <187 pg/mL who were randomly allocated to receive one tablet daily of 500 μg Β12 sublingually or orally, or two tablets daily of a vitamin B complex showed that sublingual administration was equally effective compared with oral after 8 weeks.17 In a recently published, large, retrospective study of 4281 individuals with Β12 deficiency the increase in serum B12 levels was significantly higher in the sublingual vs IM injection group (252 ± 223 vs 218 ± 184 pg/mL, p<0.001).12

Historically, IM route of vitamin B12 administration remained the gold standard for the treatment of B12 deficiency.10 Oral and sublingual routes have been proposed as they are more patient-friendly than the painful IM injections. Oral administration route of B12 is considered as the most preferable therapy in several countries such as Sweden, Norway, and Canada primarily due to significant cost savings, excellent efficacy and better safety profile with significantly lower rates of adverse events, such as pain and injection-related injuries.10,11 A cost minimization analysis, based in prescribing practices and associated expenditures in UK, disclosed that switching from IM route to oral B12 administration reduces overall expenses by 50%.15 Notably, sublingual administration is gaining increasing acceptance and is considered as an alternative effective treatment of B12 deficiency. However, almost all of the available studies have investigated sublingual B12 administration in patients with mild, subclinical B12 deficiency and had relatively short duration. Extrapolating these results to individuals with severe deficiency or malabsorptive conditions becomes challenging. In our study, sublingual B12 administration was highly effective even in subjects with very low B12 levels.

Limitations

Limitations of this study are its short-term duration and retrospective design along with the lack of a control group of patients taking or I.M B12 or placebo. In addition, a substantial proportion of participants were on metformin or PPIs and many were vegans or vegetarians, thus limiting the external validity of our findings and restricting their generalizability to more diverse populations.  Furthermore, these findings may not be generalizable to other populations with severe deficiency with megaloblastic anemia and/or neurological sequelae. In addition, we used serum B12 as a biomarker of B12 deficiency and we did not measure MMA and homocysteine.

CONCLUSION

Sublingual administration of vitamin B12 (1000 μg/day) for 3 months is highly effective in increasing serum B12 levels in patients with low B12 levels. Sublingual B12 may be considered as alternative to oral and IM administration at least in patients without megaloblastic anemia and/or neurological complications.

Acknowledgements

None.

Funding

The authors have received no payment in preparation of this manuscript.

REFERENCES

  1. Ankar A, Kumar A. Vitamin B12 Deficiency. In: StatPearls. Treasure Island (FL): StatPearls [Internet]. 2022 Oct [cited 2023 Nov 11]. Available from: https://pubmed.ncbi.nlm.nih.gov/28722952/
  2. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective Treatment of Cobalamin Deficiency With Oral Cobalamin. Blood. Blood. 1998 Aug;92(4):1191-8.
  3. Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev [Internet]. 2005 Jul [cited 2023 Nov 11]; (3) CD004655. Available from: https://pubmed.ncbi.nlm.nih.gov/16034940/
  4. Means RT, Fairfiel KM. Clinical manifestations and diagnosis of vitamin B12 and folate deficiency [Internet]. In: UpToDate, Takemoto CM (Ed), Wolters Kluwer. [Accessed 2023 Nov 29]. Available from: https://medilib.ir/uptodate/show/7155
  5. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014 Sep:349:g5226.
  6. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. 1990 Jun;34(2):99-107.
  7. Adaikalakoteswari A, Wood C, Mina TH, Webster C, Goljan I, Weldeselassie Y, et al. Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia. Sci Rep. 2020 Jul;10(1):11066.
  8. Henríquez P, Doreste J, Deulofeu R, Fiuza MD, Serra-Majem L. Nutritional determinants of plasma total homocysteine distribution in the Canary Islands. Eur J Clin Nutr. 2007 Jan;61(1):111-8.
  9. Andres E, Dali-Youcef N, Vogel T, Serraj K, Zimmer J. Oral cobalamin (vitamin B(12)) treatment. An update. Int J Lab Hematol. 2009 Feb;31(1):1-8.
  10. Elangovan R, Baruteau J. Inherited and acquired vitamin B12 deficiencies: Which administration route to choose for supplementation? Front Pharmacol. 2022 Sep:13:972468
  11. Wentworth BJ, Copland AP. Revisiting vitamin B12 deficiency: A clinician’s guide for the 21st century. Pract Gastroenterol [Internet]. 2018 [cited 2023 Nov 11];182:29. Available from: https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2020/09/B12-Deficiency-December-18.pdf
  12. Bensky MJ, Ayalon-Dangur I, Ayalon-Dangur R, Naamany E, Gafter-Gvili A, Koren G, et al. Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. Drug Deliv Transl Res. 2019 Jun;9(3):625-30.
  13. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet. 1999 Aug;354(9180):740-1
  14. Del Bo C, Riso P, Gardana C, Brusamolino A, Battezzati A, Ciappellano S. Effect of two different sublingual dosages of vitamin B(12) on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial. Clin Nutr. 2019 Apr;38(2):575-83.
  15. Tugba-Kartal A, Cagla-Mutlu Z. Comparison of Sublingual and Intramuscular Administration of Vitamin B12 for the Treatment of Vitamin B12 Deficiency in Children. Rev Invest Clin. 2020 Dec;72(6):380-5.
  16. Orhan Kiliç B, Kiliç S, Şahin Eroğlu E, Gül E, Belen Apak FB. Sublingual methylcobalamin treatment is as effective as intramuscular and peroral cyanocobalamin in children age 0-3 years. Hematology. 2021 Dec;26(1):1013-7.
  17. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8.