INTRODUCTION:

Diabetes mellitus is one of the most common of the endocrine disorders. It is a chronic condition, characterised by hyperglycaemia and due to impaired insulin secretion with or without insulin resistance¹. Type 2 diabetes mellitus is more common above the age of 40, with a peak age of onset in developed countries between 60 and 70 years, although it is being increasingly seen in younger people and even children. The prevalence of Type II diabetes varies widely in different populations, being six times more common in those of South Asian origin compared with those of Northern European origin.

It is caused by a relative insulin deficiency and insulin resistance¹. Metformin is antihyperglycemic, not hypoglycaemic. It does not stimulate insulin release from the pancreas and generally does not cause hypoglycaemia, even in large doses. Patients with renal impairment should not receive metformin. Other contraindications include hepatic disease, history of lactic acidosis, cardiac failure requiring drug therapy, or chronic hypoxic lung disease. These conditions all predispose to the potentially fatal complication of lactic acidosis. Metformin should be discontinued temporarily prior to the administration of intravenous contrast media and prior to any surgical procedure. The drug should not be re-administered any sooner than 48 hours after such procedures and should be withheld until renal function is determined to be normal. Acute side effects of metformin occur in up to 20% of patients and include diarrhoea, abdominal discomfort, nausea, metallic taste, and anorexia. These usually can be minimized by increasing the dosage of the drug slowly and taking it with meals. Intestinal absorption of Vitamin B12 and folate may be decreased during chronic metformin therapy².

Metformin associated effects:

Due to the numerous clinical benefits associated with metformin, some side effects with potential adverse health effects associated with its use are usually ignored and rarely investigated. One of the side effects is Vitamin B12 deficiency^3,4,20. Some of the mechanisms include alteration in small bowel motility, which stimulates bacterial overgrowth and consequential Vitamin B12 deficiency. Others include competitive inhibition or inactivation of Vitamin B12 absorption, alteration in intrinsic factor levels and interaction with the cubulin endocytic receptor. Also, inhibition of the calcium dependent absorption of Vitamin B12–intrinsic factor (IF) complex at the terminal ileum has been suggested as one of the mechanisms^5,6,7. Finally, decreases in both folate and Vitamin B-12 concentrations might, in turn, result in an increase in homocysteine concentrations, an independent risk factor for cardiovascular disease, especially among individuals with type 2 diabetes^8,9,18. Metformin decreases serum Vitamin B12 levels by up to 30% by inducing Vitamin B12 malabsorption^10,11,19. Metformin may induce malabsorption of Vitamin B12 by two different mechanisms. First, metformin can bind free calcium, which is required for the uptake of the Vitamin B12- intrinsic factor-complex in the ileum by its receptor¹². The second mechanism is permanent and mediated by depression of intrinsic factor secretion¹³.

MATERIALS AND METHODS:

Methodology:

An observational study conducted in the tertiary care teaching hospital. The protocol reviewed and approved by the Institutional ethics committee. This study had been conducted over the period of 12 months. Based on inclusion and exclusion criteria patients were recruited for the study. Total 102 patients had enrolled with their informed consent. Data had been collected from the Patient demographic details, clinical data, treatment chart and lab investigations etc. Based on study criteria both inpatients and outpatients of either gender had been investigated. All the patients were on chronic therapy of metformin between the age group of 18 and 65 years. In spite, of any comorbid conditions blood samples were collected for the investigations and excluded Patients who already found to Vitamin B12 deficiency, emergency visit, those who were not willing to participate in the study and those who on supplemental therapy of Vitamin B12 already. This was study also cross examined the past medical history and diet history of the patients. This was study importantly assessed the range of Vitamin B12 by the lab investigations those who are on chronic therapy of metformin. 15.68% of the patients had abnormally high level of Vitamin B12 followed by 29.41% of the patients’ boarder line of the Vitamin B12 followed by 11.76% of patients’ low range of Vitamin B12. The occurrence rate of low level of Vitamin B12 is higher in the age group between 51 and 65 years than other age group of population.

RESULT:

A total number of 102 patients with Type 2 DM included in the study (61 males, 41 females) with or without comorbid conditions.

Patient distribution according to the age group:

Patients age group between 18 and 30 years (6 males, 4 females) followed by 31 and 40 years (21 males, 14 females) followed by 41 and 50 years (19 males, 11 females) and patient age group between 51 and 65 (15 males and 12 females). Among gender, male population had higher rate of low level Vitamin B12 than female population. Moreover, Patients age group between 51 and 65 had higher rate of low level Vitamin B12 than others.

Table I: Patient wise distribution according to the age group

Age group	Male		Female
Age group	No. of patients	Mean±SD	No. of patients	Mean±SD
18-30	6	27.16 ± 2.48	4	27.75±1.70
31-40	21	36.14 ± 2.16	14	37.14±2.38
41-50	19	47.15 ± 2.73	11	47.63±1.56
51-65	15	58 ± 3.58	12	57.16±3.81
Percentage	61 (59.80%)		41(40.19%)

Patient’s distribution according to with or without co-morbid conditions:

A total number of 102 patients, among them patients diagnosed only with Type 2 DM (21 males, 14 females) and patients diagnosed Type 2 DM with co-morbid conditions (40 males, 27 females). Patients with or without comorbid conditions among them 67 are with comorbid conditions. Patients with Type 2 DM and HTN were 17 males and 13 females. Patients with comorbid conditions like Type 2 DM, HTN and IHD were 12 males and 09 females. Patients with Type 2 DM and various comorbid conditions were 11 males and 5 females.

Table II: Patient wise distribution on with or without co-morbid conditions

Gender	Type 2 DM		Type 2 DM with co-morbid conditions
Gender	No. of patients	Mean±SD	No. of patients	Mean±SD
Male	21(20.5%)	43.17±12.41	40 (39.2%)	46.02±10.29
Female	14(13.7%)	36.35±3.58	27 (26.4%)	48.40±10.39

Distribution of various Oral Hypoglycemic agents:

Various categories of Oral hypoglycemic agents prescribed, Metformin n=102 was highly prescribed than other drugs followed by Glimepiride n=51 prescribed along with metformin, followed by Vidagliptin n=3, Pioglitazone n=2, Volibose n =2.

Table III. Represents types of Oral Hypoglycemic Agents prescribed

Type of Oral Hypoglycaemic agents	Number of drugs prescribed
Metformin	102
Glimepiride	51
Pioglitazone	2
Voglibose	2
Vidagliptin	3

Distribution of Vitamin B12 range:

Investigations of Vitamin B12 had been observed, 12 Patients were on low level of Vitamin B12 (<211pg/ml) followed by 44 patients were on normal range of Vitamin B12 followed by 30 patients were on borderline of the Vitamin B12 level (211-250pg/ml) and 16 Patients were above the normal level of Vitamin B12 (>911pg/ml).

Table IV. Represents Vitamin B12 levels of the Patients.

Vitamin B12 levels (211 – 911 pg/ml)	Number of patients	Mean± SD
Low (<211 pg/ml)	12	49.16 ± 10.53
Normal (211-911 pg/ml)	44	54.68 ± 8.26
Borderline (211-250 pg/ml)	30	57.53 ± 4.55
Above Normal (>911 pg/ml)	16	51.95 ± 7.12

DISCUSSION:

An observational study conducted over the period of 12 months in a tertiary care teaching hospital. The purpose of the study is to observe and assess the range of Vitamin B12 among the Type 2 DM patients who are on the chronic therapy of the Metformin. Metformin is an euglycemic agent comes under the biguanides category belongs to oral anti-diabetic agents which is the 1^st line choice of the Type 2 DM^14,15,16. Metformin is a drug which is widely using all over the world and India among the Type 2 DM populations. Metformin has potential benefits and eventually causes potential side effects like peripheral neuropathy, abdominal discomfort include bloating, nausea, and metallic taste. Metformin side effects are usually ignored and which is not regularly monitored. Vitamin B12 deficiency leads to neurological problems like paraesthesia, ataxia, and peripheral neuropathy. Hence, our study described the Vitamin B12 levels among the Type 2 DM who were on chronic therapy of Metformin^21,22,23. Total 102 patients with or without comorbid conditions among them 67 were with comorbid conditions and remaining only with Type 2 DM. 30 Patients with Type 2 DM and Hypertension were 17(16.6%) followed by 21 patients with Type 2 DM, HTN and IHD, followed by 16 patients were with various comorbid conditions like COPD, AKI, Diabetes ketoacidosis, Pulmonary TB, Chronic liver disease, Alcoholic liver disease, anaemia, Hypothyroidism and diabetic foot²⁴. Various categories of Oral hypoglycaemic agents prescribed, most prescribed drug was metformin followed by combination of glimepiride with metformin was the second most prescribed drugs followed by Volibose, Pioglitazone and Vidagliptin were prescribed least. Investigations of Vitamin B12 had been observed and based on the patients value the level of Vitamin B12 had been categorized, 12 Patients were on low level of Vitamin B12(<211pg/ml) followed by 44 patients were on normal range of Vitamin B12 followed by 30 patients were on borderline of the Vitamin B12 level (211-250 pg/ml) and 16 Patients were above the normal level of Vitamin B12(>911pg/ml). Dietary history might be impacted on those who were found to be above the normal level and low level of Vitamin B12.

CONCLUSION:

The study concluded that higher doses with chronic therapy of Metformin may have interferes Vitamin B12 level. Some of the patients had abnormally higher value of Vitamin B12 due to their diet which also has some impact on Vitamin B12. However, there will be higher chance of metformin associated effect on Vitamin B12 with high doses of metformin and importantly patients who were with comorbid conditions. Moreover, age also important factor that the study reveals among gender, male patients population has higher rate of low level Vitamin B12 than female population. Patient’s age group between 50 and 65 were having higher rate of low level Vitamin B12 than others and patients with other comorbid condition also had low level and borderline of Vitamin B12. Hence, further investigations are required. So, this study concluding that chronic therapy of metformin required regular check on Vitamin B12 among Type 2 DM patients.

CONFLICT OF INTEREST:

Authors have no conflict of interest over the study.

ACKNOWLEGEMENT:

I thank Almighty who has given the knowledge and wisdom to finish this study successfully. I would like express the gratitude to my guide Dr. G Veeramani, M.Pharm, Ph.D, and extending gratitude to my co-guide Dr. K Manjanna M.Pharm, Ph.D, I thank Dr. G.P Mohanta M.Pharm, Ph.D, who has given opportunity to work on this plate form. Last but not least I have immensely expressing my thanks to my family & my wife Mrs. Rosy Andrew B.Pharm, MBA, for their support in all aspects.

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Received on 12.03.2023 Modified on 10.06.2023

Research J. Pharm. and Tech 2024; 17(5):2099-2102.

DOI: 10.52711/0974-360X.2024.00332