1. Metformin and Vitamin B12 deficiency
Dr Hiren Patt
D.M. (Endocrinologist)
Satellite, A’bad

2. Case 54 yrs/M, strict vegeterian, DM: 8 yrs
Burning feet, fatigue, bodyache
Rx:
Metformin (2 gms/day)
Glimiperide (2 mg/day)
HbA1c: 8.6 %
FBS: 158 mg/dl

3. PNS Examination
Ankle jerk: absent
Vibration & light touch: reduced

4. Management DM control (strict) Pregabalin/gabapentin What else ?
Vitamin B12

5. Trends in Diabetes Mellitus

6. OAD
Metformin SU
DPP4i
SGLT2i
GLP1 Ra
TZD

7. OAD
Metformin: 1st line agent SU
DPP4i
SGLT2i
GLP1 Ra
TZD

8. Metformin: Concerns G.I. side effects Lactic acidosis: very rare
Vitamin B12 deficiency

9. Vit B12 deficiency & Metformin
Prevalence: Upto 30 %
Reduction in Vit B12 levels: as early as 3-6 months
Symptoms: 4-6 yrs (because of hugh stores)
Predictors:
Dose > 1 gm/day
Duration > 4 yrs

10. How Metformin leads to B12 deficiency ?

11. Metformin: Prevents B12 Absorption

13. Metformin: Prevents B12 Absorption

14. Clinical Features of Vitamin B12 Deficiency
Neuropsychiatric
Cognitive impairment
Gait abnormalities
Irritability
Peripheral neuropathy
Weakness
Cutaneous
Hyperpigmentation
Gastrointestinal
Glossitis
Jaundice
Hematologic
Anemia (macrocytic, megaloblastic)
Thrombocytopenia
So what are the clinical features to be looked out to diagnose Vitamin B12 deficiency? This smart chart shows the clinical features of vitamin B12 deficiency
Neuropsychiatric
Cognitive impairment
Gait abnormalities
Irritability
Peripheral neuropathy
Weakness
Cutaneous
Hyper pigmentation
Vitiligo
Gastrointestinal
Glossitis
Jaundice
Hematologic
Anemia (macrocytic, megaloblastic)
Thrombocytopenia
References:
Langan RC. Update on Vitamin B12 Deficiency. AAFP. 2011; 83(12):

15. Importance of Dx: Vit B12 deficiency
Neurological symptoms may present even in the absence of anemia
Mimic Diabetic neuropathy
Irreversible neurological damage, if left untreated

16. Stages of B12 induced Peripheral Neuropathy
Demyelination
Axonal damage
Neuronal death

17. Serum Cobalamin (Cbl) Levels
Serum Cbl level*
Type of result
Cbl deficiency
> 300 pg/ml
Normal
Unlikely
200 – 300 pg/ml
Borderline
Deficiency possible
< 200 pg/ml
Low result
Consistent with Cbl deficiency
Checking Serum Cobalamin (Cbl) Levels is useful for diagnosing MICD.
Normal Cbl levels is >300 pg/ml
Serum Cbl levels < 200 pg/ml is suggestive of Cbl deficiency. While pg/ml levels are borderline.
However, Different laboratories use different methods to calculate the Cbl levels. As a result there is no common reference range or “gold standard test”
Reference:
Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract ;97(3):
*Different laboratories use different methods to calculate the Cbl levels. As a result there is no common reference range or “gold standard test”
Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):

18. Rx: Vit B12 1000 mcg (1 mg) every day for one week initially
Parenteral route is the preferred route for patients with neurological defects Duration of dose depends on the removal of metformin.
1000 mcg (1 mg) every day for one week initially
Followed by 1 mg every week for 4 weeks
Parenteral route is the preferred route for patients with neurological defects
1000 mcg (1 mg) every day for one week initially
Followed by 1 mg every week for 4 weeks
Duration of dose depends on the removal of metformin. If metformin has to be continued, appropriate Cbl replacement should also be given.
Reference:
Mazokapakis E. Recommendations for the diagnosis and management of metformin- induced vitamin B12 (Cbl) deficiency. Diabetes research and clinical practice. 2012; 97:
If metformin has to be continued, appropriate Cbl replacement should also be given
Mazokapakis E. Recommendations for the diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes research and clinical practice. 2012; 97:

19. What About Oral Vit B12 ?
Few studies have shown equal efficacy with high dose oral B 12 (1-2 mg) compared to Inj B12, even in patients with malabsorption (pernicious anemia)

20. Response to Vit B12 Therapy
Laboratory studies should be monitored after Cobalamin therapy to document a haematological and metabolic response
Elevated levels of iron, indirect bilirubin & Decrease in LDH levels
Hyper segmented Neutrophils disappear
3 months
Day 10-14
Day 3-7
Day 1-2
Laboratory studies should be monitored after Cobalamin therapy to document a haematological and metabolic response.
Day 1-2: Look for Elevated levels of iron, indirect bilirubin, Decrease in LDH levels, with parenteral Cbl; bone marrow erythropoiesis also changes from megaloblastic to normoblastic during this period. Patient may feel better long before any changes in the degree of anaemia happened!
Day 3-7: Reticulocytosis, Rise in hemoglobin, Decrease in MCV
Day 10-14: Hyper segmented Neutrophils disappear
3 months: Neurological symptoms improve by 3 months. Maximum improvement seen in 6-12 months. The degree of improvement is inversely related to the extent and duration of the disease.
Reference:
Mazokapakis E. Recommendations for the diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes research and clinical practice. 2012; 97:
Neurological symptoms improve by 3 months.
Maximum improvement seen in 6-12 months
Reticulocytosis
Rise in hemoglobin
Decrease in MCV
Mazokapakis E. Recommendations for the diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes research and clinical practice. 2012; 97:

21. Prevention Serum Vit B12 level: once a year or
Inj. Vit B mcg: once a year

22. Take Home Messages Impact of diabetes is growing alarmingly in India
Metformin is the first line drug commonly prescribed for T2DM and can cause MICD
Appropriate measures should be taken to prevent and treat MICD so that it doesn’t lead to neuropathy
Taking home messages:
Impact of diabetes is growing alarmingly in India
Metformin is the first line drug commonly prescribed for T2DM and can cause MICD
Appropriate measures should be taken to prevent and treat MICD so that it doesn’t lead to neuropathy – cobalamin supplementation should be appropriately added to patient’s treatment

23. 4/11/2019