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

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

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

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

Trends in Diabetes Mellitus

OAD Metformin SU DPP4i SGLT2i GLP1 Ra TZD

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

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

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

How Metformin leads to B12 deficiency ?

Metformin: Prevents B12 Absorption

Metformin: Prevents B12 Absorption

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):1424-29

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

Stages of B12 induced Peripheral Neuropathy Demyelination Axonal damage Neuronal death

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 200-300 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. 2012;97(3):359-67. *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):359-67.

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; 97:359-67. 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; 97:359-67.

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)

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; 97:359-67. 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; 97:359-67.

Prevention Serum Vit B12 level: once a year or Inj. Vit B12 1000 mcg: once a year

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

4/11/2019