Annals of Clinical Nutrition and Metabolism : eISSN 2799-8363 / pISSN 2799-7898

Table. 2.

Table. 2.

Literature evaluations of drug-induced vitamin deficiencies

Vitamin depleted Causative medications Study design Patients (or participants) Interventions Relevant study outcomes Results References
Vitamin A Orlistat Meta-analysis 10,631 participants from 16 trials (average BMI: 36.3 kg/m2) Orlistat 120 mg three times daily Levels of fat‐soluble vitamins (A, D, E) and beta‐carotene Orlistat therapy was associated with lower fat‐soluble vitamin and beta‐carotene levels [2]
RCT Patients aged 30~60 years with BMI ≥30 kg/m2 Orlistat 120 mg three times daily for 4 years Changes in plasma levels of fat-soluble vitamins Significant decreases in vitamin A in the orlistat group compared with the placebo group (−0.22 vs. −0.19 μmol/L, P<0.05) [3]
Cholestyramine RCT 303 patients with hypercholesterolemia Dietary advice plus cholestyramine (8 to 16 g/d for 2 months) Serum concentrations of vitamin E, β-carotene, lycopene, and vitamin A 40% decrease in mean serum β-carotene (P<0.001) and 5% increase in vitamin A (P<0.001) after 2 months on cholestyramine [7]
Vitamin D Corticosteroids Cross-sectional NHANES participants 2001~2006 (n=22,650) Prevalence of low 25(OH)D level (<10 ng/mL) 11% in steroid users vs. 5% in non-users (P=0.009) [62]
AEDs Cross-sectional 58 patients on antiepileptic therapy Serum 25(OH)D level
Frequency of 25(OH)D <20 ng/dL
Lower levels of 25(OH)D in AED users vs. control patients (28.2±10.3 ng/mL vs. 34.4±12.7 ng/mL; P=0.02)
20 (34.4%) of AED users vs. 2 (6.8%) of controls had 25(OH)D levels <20 ng/dL (P=0.01)
Orlistat RCT 30 obese subjects with a mean BMI of 47 kg/m2 Orlistat 120 mg three times daily for 1 year Serum levels of calcitriol 140±39 pmol/L at baseline vs. 111±45 pmol/L after 1 year of orlistat therapy (P<0.05) [68]
Cholestyramine RCT 268 men aged 42~68 years Cholestyramine vs. placebo for 7~10 years Plasma levels of calcitriol 99±190 pmol/L in placebo vs. 91±56 pmol/L in the cholestyramine group (NS) [67]
Vitamin K Antibiotics RCT Critically ill children who received antibiotic therapy for a minimum of 14 days Single dose of prophylactic vitamin K on day 1 of antibiotic therapy Incidence of vitamin K deficiency 15% of the total study population
13.3% vs. 16.7% in those with or without prophylactic vitamin K treatment, respectively (P=0.79)
Nested case-control Patients aged ≥20 years with or without a hemorrhagic event after using cephalosporins Risk of a hemorrhagic event aOR 1.71 (95% CI, 1.42~2.06) with the use of cephalosporins [73]
Orlistat RCT Patients aged 30~60 years with BMI ≥30 kg/m2 Orlistat 120 mg three times daily for 4 years Changes in plasma levels of the fat-soluble vitamins Significant decreases in vitamin K1 in the orlistat group compared with the placebo group (−0.08 vs. 0.07 μg/L, P<0.001) [3]
Vitamin B1 Furosemide Prospective cohort 50 patients >18 years of age with an ICU stay of at least 48 hours Diuretic group (furosemide 20~160 mg/d) vs. control group Mean serum thiamin levels in the baseline and post–ICU admission days 2, 5, and 10 The diuretic group had significantly lower serum thiamin levels than the control (15.5±10.7 vs. 46.8±29.5 ng/mL; P<0.001 at baseline, 23.2±15.4 ng/mL vs. 49.0±38.0 ng/mL; P< 0.05 on day 2) [10]
Fluorouracil Retrospective chart review 18 patients developed Wernicke-Korsakoff Syndrome during cancer treatment (5 of whom were taking fluorouracil) Serum thiamin concentration All patients who measured serum thiamine level (n=16) had abnormally low levels of serum thiamine (<7 nmol/L) [17]
Vitamin B3 Isoniazid, pyrazinamide Case report 69-year-old female with cardiac, lung, and cutaneous sarcoidosis Decreased serum nicotinic acid levels (4.5 μg/dL) after isoniazid therapy [21]
Vitamin B6 Isoniazid Single-arm clinical trial 20 patients with pulmonary tuberculosis One week of therapy including isoniazid Plasma levels of PLP Decreased PLP levels in 18 patients (15 nmol/L at baseline vs. 11 nmol/L at 1 year, P<0.001) [24]
AEDs Cross-sectional Patients with epilepsy Converted from an inducing AED (phenytoin, carbamazepine) to a non- inducing AED (levetiracetam, lamotrigine, or topiramate) Prevalence of low vitamin B6 (<5 ng/mL) 16/33 (48%) with epilepsy vs. 1/11 (9%) of normal subjects (P<0.05) had low vitamin B6 levels
Only 21% of patients had a low vitamin B6 level after switching to a non-inducing AED (P<0.05)
Levodopa Case report A 75-year-old man with advanced Parkinson’s disease Levodopa/carbidopa 200/20 mg/d for 45 months Serum vitamin B6 levels were undetectably low (<2.0 ng/mL) but normalized after vitamin B6 supplementation [29]
Theophylline Single-arm clinical trial 7 healthy males 15 weeks of theophylline treatment Mean plasma and erythrocyte PLP levels Erythrocyte PLP levels declined from 303.3±73.2 pmoL/g to 185.1±69.2 pmoL/g within 52 days of treatment (P=0.015)
Plasma PLP levels declined from 62.6±26.8 nmol/L to 29.7±14.1 nmol/L within 32 days of treatment (P=0.015)
Vitamin B7 AEDs Cross-sectional 12 adults with seizures requiring AEDs for more than 1 year AEDs (carbamazepine, phenytoin, phenobarbital, valproic acid, and felbamate) Urinary excretion of biotin metabolites There was 2.5-fold greater urinary excretion of biotin metabolites in the anticonvulsant-treated group than the control group [33]
Vitamin B9 Methotrexate RCT 113 patients with rheumatoid arthritis Methotrexate of 7.5~25 mg/wk with or without folate supplement Plasma homocysteine and folate levels A decrease in serum folate level by 4.1 nmol/L (95% CI, –7.6 to –0.6) and a 3.6 μmol/L (95% CI, 1.7 to 5.6) increase in homocysteine [40]
Sulfonamides Cross-sectional 23 outpatients with ulcerative colitis treated with sulfasalazine vs. 20 healthy controls Blood concentrations of folate UC patients had significantly lower folate concentrations than controls (9.8±7.3 pmol/mL vs. 23.5±9.6 pmol/mL, P=0.015) [44]
AEDs Prospective AED-treated patients (n=2,730) vs. AED-untreated patients with epilepsy (n=170) vs. healthy controls (n=200) AEDs (carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate) Mean serum folate level Mean folate level was 6.0±3.5 ng/mL in the AED-treated group vs. 6.6±3.7 ng/mL in untreated patients (P=0.044) [45]
Vitamin B12 Acid-suppressive agents (PPIs, H2RAs) Meta-analysis Four case–control studies and one observational study Prolonged acid-suppressive agents use Risk of vitamin B12 deficiency HR 1.83 (95% CI, 1.36~2.46) [48]
Case-control Patients aged ≥20 years Risk of vitamin B12 deficiency OR 1.65 (95% CI, 1.58~1.73) with ≥2 years use of PPIs
OR 1.25 (95% CI, 1.17~1.34) with ≥2 years use of H2RAs
Case-control Patients aged ≥65 years Risk of vitamin B12 deficiency OR 4.45 (95% CI, 1.47~13.34) with ≥12 months use of H2RAs and/or PPIs [50]
Metformin RCT Patients with type 2 diabetes under insulin treatment Metformin 850 mg or placebo three times a day for 4.3 years Percentage change in vitamin B12 from baseline 19% decrease in vitamin B12 level compared with placebo (P<0.001) [53]
RCT Impaired glucose tolerance and FBG of 95~125 mg/dL, aged ≥25 years, BMI ≥24 kg/m2 Metformin 850 mg or placebo twice daily Incidence of vitamin B12 deficiency (≤203 pg/mL) 4.3% of patients in the metformin group vs. 2.3% of patients in the placebo group had vitamin B12 deficiency at the 5-year follow-up (P=0.02) [54]
Nested case-control Patients with diabetes receiving metformin treatment Risk of vitamin B12 deficiency aOR 2.88 (P<0.001) with 1 g/d metformin dose increment
aOR 2.39 (P=0.001) for those patients using metformin for ≥3 years

BMI = body mass index; RCT = randomized clinical trial; NHANES = National Health and Nutrition Examination Survey; NS = not significant; 25(OH)D = 25-hydroxyvitamin D3; AEDs = antiepileptic drugs; ICU = intensive care unit; PLP = pyridoxal phosphate; PPIs = proton pump inhibitors; H2RAs = H2-receptor antagonists; FBG = fasting blood glucose; HR = hazard ratio; OR = odds ratio; aOR = adjusted odds ratio; CI = confidence interval.

Ann Clin Nutr Metab 2022;14:20-31
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