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ORIGINAL ARTICLE
Year : 2022 | Volume
: 13
| Issue : 4 | Page : 347-352
Comparison of the efficacy of oral methylcobalamin tablets vs. nasal spray (NASO B12) in diabetic patients on metformin therapy
Syed Salman Farookh, CR Jayanti, A Geetha
Department of Pharmacology, Bangalore Medical College and Research Institute, Bengaluru 560002, Karnataka, India
Correspondence Address:
Dr. Syed Salman Farookh
Department of Pharmacology, Bangalore Medical College and Research Institute, Bengaluru 560002, Karnataka
India
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jod.jod_92_22
Context: Metformin is known to increase in the risk of developing vitamin B12 deficiency. This study aimed to compare the effectiveness of nasal spray of methylcobalamin (NASO B12) and methylcobalamin tablets for treating vitamin B12 deficiency in diabetic patients receiving metformin. Materials and Methods: In this parallel-group, comparative, open-label clinical study, patients (n = 100) were assigned to two groups: nasal spray of methylcobalamin (NASO B12) (methylcobalamin 250 µg/spray), sprayed in each nostril every alternate day for a total of seven doses (Group 1: a total of 3500 µg methylcobalamin per patient) and oral methylcobalamin tablets, a single daily dose of 1500 µg for a total of seven doses (Group 2: a total of 10,500 µg methylcobalamin per patient). The assessment of efficacy was carried out by measuring serum vitamin B12 levels at baseline, day 7, and day 14. Statistical Analysis Used: The analysis used is Student’s unpaired t-test. Results: NASO B12 treatment resulted in vitamin B12 levels of ≥400 pg/mL (recently updated normal levels as per American Academy of Family Physicians) in 86% and 92% of patients, on day 7 and day 14, respectively, whereas no patient attained ≥400 pg/mL with oral therapy. NASO B12 therapy resulted in higher mean vitamin B12 levels of 485.88 and 570.16 pg/mL when compared with 172.26 and 185.44 pg/mL with oral tablets on day 7 and day 14, respectively. Conclusion: NASO B12 provided much superior absorption of vitamin B12 when compared with oral vitamin B12 tablets and can be used as an effective alternative.
Keywords: Diabetes, efficacy, metformin, methylcobalamin, nasal therapy, NASO B12
NASO B12 provided much superior absorption of vitamin B12 when compared with oral vitamin B12 and can be used as an effective alternative.
IntroductionVitamin B12 is essential for DNA synthesis, red blood cell formation, and neurologic function[1] and is also involved in the metabolism of fat and carbohydrate.[2],[3]
The clinical manifestations of vitamin B12 deficiency are the effects of depletion on multiple systems, and their severity varies greatly. The clinical manifestations are heterogeneous, but they can also differ depending on the grade and duration of the deficiency. Mild deficiency causes fatigue and anemia, with indices indicating vitamin B12 deficiency but no neurological symptoms. Moderate deficiency may include obvious macrocytic anemia, glossitis, as well as some mild or subtle neurological features, such as distal sensory impairment.[4],[5] Severe deficiency is characterized by bone marrow suppression, neurological features, and the risk of cardiomyopathy. However, it is critical to recognize that clinical symptoms of deficiency can manifest without anemia or low serum vitamin B12 levels. In these cases, treatment should be initiated as soon as possible.[4]
The etiology of vitamin B12 deficiency typically includes malabsorption-related causes such as autoimmune gastritis (pernicious anemia), celiac disease, inflammatory bowel disease, surgical gastrectomy, gastric bypass, and ileal resection. Vitamin B12 deficiency can occur less frequently as a result of nutritional habits (strict vegans, breastfed infants born to vegan mothers with reduced dietary intake of animal products), drug interference (metformin, proton pump inhibitors, drug-affected purine, and pyrimidine synthesis), inherited disorders affecting intrinsic factor (IF) and other inherited disorders including methylmalonic acidemia and transcobalamin II deficiency nitrous oxide abuse, Diphyllobothrium latum infection, and pancreatic insufficiency.[6]
Metformin is considered a cornerstone in the treatment of diabetes and is the most frequently prescribed first-line therapy for individuals with type 2 diabetes. In addition, it is one of a few antihyperglycemic agents associated with improvements in cardiovascular morbidity and mortality, which is a major cause of death in patients with type 2 diabetes.
Metformin induces vitamin B12 malabsorption, which may increase the risk of developing vitamin B12 deficiency, a clinically important and treatable condition. It has been reported that an average of 6–30% of patients could show vitamin B12 deficiency due to metformin use.[7],[8] As per UK MHRA, decreased vitamin B12 levels, or vitamin B12 deficiency, are now considered to be a common side effect in patients on metformin treatment, especially in those receiving a higher dose or longer treatment duration and in those with existing risk factors. Accordingly, it has issued new advice to check vitamin B12 serum levels in patients being treated with metformin who have symptoms suggestive of vitamin B12 deficiency.[9]
The proposed mechanisms to explain metformin-induced vitamin B12 deficiency among patients with T2DM include alterations in small bowel motility, which stimulates bacterial overgrowth and consequential vitamin B12 deficiency, competitive inhibition or inactivation of vitamin B12 absorption, alterations in IF levels, and interaction with the cubulin endocytic receptor. Metformin has also been shown to inhibit the calcium-dependent absorption of the vitamin B12–IF complex at the terminal ileum. This inhibitory effect is reversed with calcium supplementation.
Oral tablets and intramuscular injections have been the mainstay of treatment of vitamin B12 deficiency. Intramuscular injections are generally inconvenient due to pain and require healthcare professionals for administration, thus increasing the economic burden on patients which ultimately leads to discontinuation of the treatment. The efficacy of oral supplementation of vitamin B12 is limited by factors such as the absence of IF, gastric surgery, concomitant metformin, or antacid treatment.
To overcome the shortcomings of the oral and intramuscular formulations of vitamin B12, a nasal spray of methylcobalamin (NASO B12; methylcobalamin 250 µg/spray) has been developed by Troikaa Pharmaceuticals Limited and has recently been approved for the treatment of vitamin B12 deficiency. NASO B12 has been shown to be rapidly absorbed and highly effective in the treatment of vitamin B12 deficiency. The rapid increase in vitamin B12 levels produced by NASO B12 has resulted in a steady increase in hemoglobin levels.[10]
As absorption of vitamin B12 from NASO B12 bypasses the gastrointestinal tract in which the mechanisms of metformin-induced vitamin B12 deficiency are proposed and take place from the nasal epithelium. It was hypothesized that NASO B12 will be more effective in treating the deficiency of vitamin B12, when compared with oral methylcobalamin in patients receiving metformin.
The goal of this study was to compare the efficacy and safety of NASO B12 with oral methylcobalamin tablets in treating the deficiency of vitamin B12 in patients receiving metformin for the management of diabetes.
Materials and MethodsInvestigational products
The products include methylcobalamin (250 µg/spray) nasal spray (NASO B12; manufactured and marketed by Troikaa Pharmaceuticals Ltd., Ahmedabad, India) and methylcobalamin 1500 µg oral tablet (Meconerve® 1500 from Micro Labs Ltd).
Overview of the study design
It was a prospective, randomized, parallel-group, comparative, open-label clinical study. This study was conducted at the Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India, with patient enrolment from February 2021 (first patient in) to July 2021 (last patient out). One hundred type 2 diabetes mellitus patients on metformin ≥4 months with vitamin B12 deficiency were enrolled in this study and randomized equally into two groups. According to the randomization procedure, Group 1 was assigned to the novel methylcobalamin nasal spray (NASO B12) and Group 2 was assigned to methylcobalamin oral tablet for the treatment of vitamin B12 deficiency during the study period of 15 days [Figure 1].
Study population
Patient eligibility
Diabetic individuals of either sex (age >18 years; non-pregnant females) on metformin therapy (≥ 1000 mg/day) for more than 4 months and have vitamin B12 level <210 pg/mL (155 pmol/L) were included for the study.
Patients with known hypersensitivity or allergies to cobalt and/or vitamin B12 or any component of the study medication, having any significant nasal pathology/chronic nasal symptoms/nasal allergies/upper respiratory tract infections, using any nasal medication/device, having a known diagnosis of severe renal impairment or renal failure, or on treatment with drugs which interfere with vitamin B12 assay were excluded from the study. Patients who participated in any clinical trial within the last 30 days at the time of screening and had any disorder or condition that in the opinion of the investigator would prohibit study participation or affect study outcome were also excluded.
Study procedure
The patients who were found to be eligible were explained about the study in detail. A written consent obtained from the interested participants prior to any study procedure. Patients were screened to confirm their eligibility as per the inclusion and exclusion criteria.
All patients enrolled in this study were subjected to receive either of the allotted study treatments after the enrolment procedure. First dose of the treatment was taken in the presence of the investigator to ensure the correctness of the dosing method and the remaining doses were to be self-administered at home. The patients assigned to Group 1 received a commercially available formulation of methylcobalamin (250 µg/ spray) nasal spray (NASO B12) in each nostril every alternate day for a total of seven doses during the study period (a total of 3,500 µg of methylcobalamin per patient). The patients, assigned to oral methylcobalamin tablets (Group 2), received a single daily dose of commercially available 1500 µg methylcobalamin tablets, for a total of seven doses during the study period (a total of 10,500 µg of methylcobalamin per patient). Fixed-dose combinations and nutritional/dietary supplements containing any form of vitamin B12 were not allowed during the study period.
The assessment of efficacy was carried out by measuring serum vitamin B12 levels. Serum vitamin B12 levels were assessed at baseline, day 7, and day 14.
Safety was assessed by recording the number and severity of adverse events as reported by the patient at any time of the study.
Outcomes
The main outcome was the proportion of patients with normalized serum vitamin B12 levels (≥400 pg/mL) at 7 and 14 days. The secondary outcomes were the mean serum vitamin B12 levels (pg/mL) and the number of adverse events.
Statistical analysis
The serum vitamin B12 levels between both the treatments were compared (baseline, day 7, and day 14) using Student’s unpaired t-test.
Results and DiscussionSubject demographics and disposition
One hundred patients who met the selection criteria participated in the study. All the patients completed the study, and data of the 100 patients who completed the study were considered for analysis. Baseline demographic data of the study populations are given in [Table 1].
Efficacy outcomes
About 86% of patients achieved vitamin B12 levels of ≥400 pg/mL on day 7 of NASO B12 spray therapy (three doses). Around 92% of patients achieved vitamin B12 levels of ≥400 pg/mL on day 14 of NASO B12 spray therapy (seven doses). No patient on day 7 and day 14 achieved vitamin B12 levels ≥400 pg/mL with marketed oral tablets therapy [Figure 2].
Figure 2: Percentage of patients achieving vitamin B12 levels ≥ 400 pg/mL on day 7 and day 14 of therapy with methylcobalamin oral tablets and NASO B12 sprayThe mean serum vitamin B12 concentration for both treatments is shown in [Figure 3]. The mean ± SD baseline plasma vitamin B12 levels for the test (NASO B12) and reference (oral) products were 134.94 ± 25.51 and 132.56 ± 27.72 pg/mL, respectively. There was no significant difference in baseline serum vitamin B12 levels of both treatment groups. NASO B12 resulted in higher vitamin B12 concentrations of 485.88 pg/mL on day 7 and 570.16 pg/mL on day 14, whereas the concentrations of vitamin B12 were 172.26 and 185.44 pg/mL with methylcobalamin tablets on day 7 and day 14, respectively. Mean values of serum vitamin B12 were significantly higher for NASO B12 on day 7 and day 14 when compared with oral therapy (P < 0.00001). Thus, absorption of vitamin B12 is significantly higher by NASO B12 when compared with methylcobalamin tablets. Treatment with NASO B12 corrected vitamin B12 deficiency in 7 days (three doses), and the elevated levels were maintained with subsequent doses.
Figure 3: Mean levels of vitamin B12 in deficient patients at baseline, day 7, and day 14 with methylcobalamin oral tablets and NASO B12 spray therapyBoth the treatments were well tolerated and there were no adverse events observed throughout the study duration.
DiscussionAbsorption of vitamin B12 by the oral route is highly variable, and hence tablets of vitamin B12 do not provide a predictable increase of vitamin B12 in the body even upon long-term administration. As a result, vitamin B12 injections are the mainstay to treat deficiency of vitamin B12. However, vitamin B12 injections are very painful. Besides, the patient has to make frequent visits to the clinic to take the doses.
As a result of these shortcomings, patient compliance is a major issue with oral and parenteral formulations of vitamin B12.
Metformin therapy in diabetic patients has been linked to vitamin B12 deficiency.[8] Several mechanisms in the intestine have been proposed to be linked to the inhibition of absorption of vitamin B12 in the presence of metformin.
NASO B12 is a painless, reliable, and easy-to-administer alternative to oral and parenteral formulations of vitamin B12.
Unlike oral vitamin B12 therapy, NASO B12 assures rapid, consistent, predictable, and dependable absorption. NASO B12 can be self-administered with high compliance. It can be self-administered by all patients including those who have swallowing difficulties, nausea or vomiting, or absorption issues such as pernicious anemia, post-bariatric surgery, or malabsorption.[10]
In comparison to injectable vitamin B12 therapy, NASO B12 is pain-free, is self-administered, costs less, and saves patients’ multiple visits to the doctor.
Its safety and efficacy have been tested in two clinical studies. The results of these studies proved that NASO B12 is rapidly absorbed and corrects the vitamin B12 deficiency rapidly and is safe and well tolerated.[10],[11]
The present study compared the efficacy of NASO B12 and oral supplementation of vitamin B12 in treating the vitamin B12 deficiency in type 2 diabetes mellitus patients on metformin therapy. To the best of our knowledge, this is the first study comparing the efficacy of nasal vitamin B12 therapy with oral vitamin B12 therapy in type 2 diabetes mellitus patients on metformin and having vitamin B12 deficiency.
NASO B12 has been shown to treat vitamin B12 deficiency in just seven doses administered on alternate days.[10] Whereas oral therapy is recommended for daily dosing.[12] Thus this study was intended to compare the efficacy of seven daily doses of 1500 µg tablets and seven doses of NASO B12 (500 µg every alternate day) in treating the vitamin B12 deficiency.
Recently, the American Academy of Family Physicians has redefined the normal, low-normal, and low values of serum vitamin B12 levels to be ≥ 400, 150–399, and <150 pg/mL, respectively. In line with the above recommendation, the normal levels of serum vitamin B12 in the study were considered to be ≥ 400 pg/mL.[1]
The results indicate that in spite of the fact that the total dose of methylcobalamin in the oral treatment arm was three times (10,500 µg) to that of NASO B12 (3,500 µg), none of the patients achieved normal vitamin B12 levels with oral treatment of 7 days. In contrast, 86% and 92% of the patients achieved normal serum vitamin B12 levels in three and seven doses, respectively. In this study, 92% of the patients achieved serum vitamin B12 levels ≥ 400 pg/mL with NASO B12, indicating low variability in efficacy.
The superior efficacy of NASO B12 was again established by the increase in mean serum vitamin B12 levels. There was a mean increase of only 39.7 and 52.9 pg/mL in serum vitamin B12 levels on day 7 and day 14 in the oral treatment arm, whereas a very high increase of 350.9 and 435.2 pg/mL in serum vitamin B12 levels was observed on day 7 and day 14, respectively, in the NASO B12 treatment arm.
The serum vitamin B12 levels of 485.88 and 570.16 pg/mL obtained in the study on days 7 and 14, respectively, with NASO B12 treatment are in line with levels obtained in another study in the literature by Seth et al.[10]
There were no adverse events reported in the study, and both NASO B12 and vitamin B12 oral tablets were found to be well tolerated.
It is noteworthy that proper patient counseling results in better patient acceptance and compliance. There is an occasional outflow of the red-colored drug solution from the nose after administration of NASO B12. It is advisable to counsel the patients that the red-colored fluid is the extra drug which is naturally red in color and is of no concern. Further, patients who are hesitant of taking nasal formulations should be made aware that the only other option is vitamin B12 injections and they are painful. Hot foods may cause nasal secretions and a resulting loss of medication; therefore, patients should be told to administer NASO B12 nasal spray at least 30 min before and after ingestion of hot foods or liquids.
In a prospective, multicentric, clinical study, Seth et al. found that in vitamin B12-deficient patients, seven doses of NASO B12 on alternate days corrected the vitamin B12 levels, and weekly maintenance therapy of NASO B12 500 µg/dose for 4 weeks was able to maintain the levels (>200 pg/mL). Further, NASO B12 was well-tolerated throughout the treatment period.[10]
Patients on metformin therapy receiving NASO B12 should also be instructed that they will require weekly intranasal administration of NASO B12 spray in each nostril after correction of vitamin B12 deficiency for the remainder of their lives. Failure to do so will result in the return of the anemia and in the development of incapacitating and irreversible damage to the nerves of the spinal cord. Also, the patients should be warned about the danger of taking folic acid in place of vitamin B12, because the former may prevent anemia but allow progression of subacute combined degeneration of the spinal cord.
Thus, NASO B12 is found to be effective in treating the deficiency of vitamin B12 in type 2 diabetes mellitus patients on metformin therapy. Our study has some limitations. Clinical symptoms and hematology parameter which could have validated improvement in vitamin B12 levels by NASO B12 before and after treatment were not studied. Further studies can be carried out to confirm the long-term safety of nasal formulation.
ConclusionThe study results indicate that NASO B12 provides absorption of substantially higher amounts of methylcobalamin when compared with that provided by methylcobalamin tablets. Therefore, NASO B12 is highly effective in treating the vitamin B12 deficiency when compared with the oral treatment in type 2 diabetes mellitus patients on metformin therapy and would be a game changer in overcoming the limitations of oral and intramuscular treatment of vitamin B12.
Acknowledgements
The authors are thankful to the Nursing team and supporting staff at the Bangalore Medical College and Research Institute and to the volunteers for their participation in the study.
Financial support and sponsorship
Nil.
Conflicts of interest
All authors declare that they have no conflicts of interest.
Authors’ contribution
SF: conceptualization, methodology. CRJ: data curation, writing-original draft preparation. AG: writing-reviewing and editing.
Compliance with ethical standards
Clinical Trials Registry: CTRI/2021/01/030204.
Ethics Committee Approval: BMCRI/PS/184/2020–21.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
References
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