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Vitamin B12 in type 2 diabetic patients treated with metformin
Vitamina B12 en pacientes diabéticos tipo 2 en tratamiento con metformina
José María Calvo Romero
, José Manuel Ramiro Lozano
Corresponding author
Servicio de Medicina Interna, Hospital Ciudad de Coria, Coria, Cáceres, Spain
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"José María Calvo Romero, José Manuel Ramiro Lozano" "autores" => array:2 [ 0 => array:4 [ "nombre" => "José María" "apellidos" => "Calvo Romero" "email" => array:1 [ 0 => "jm.calvo@orangemail.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "José Manuel" "apellidos" => "Ramiro Lozano" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Medicina Interna, Hospital Ciudad de Coria, Coria, Cáceres, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vitamina B<span class="elsevierStyleInf">12</span> en pacientes diabéticos tipo 2 en tratamiento con metformina" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Vitamin B<span class="elsevierStyleInf">12</span> deficiency is relatively common, particularly in the elderly.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Its clinical signs are mainly hematological and neuropsychiatric in nature, and may sometimes be difficult to detect. Vitamin B<span class="elsevierStyleInf">12</span> deficiency is usually due to vitamin malabsorption arising from various causes, including the classical pernicious anemia (PA).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">As far back as 1971 it was reported that 4 (5.6%) out of 71 diabetic patients on long-term treatment with metformin had low plasma vitamin B<span class="elsevierStyleInf">12</span> levels due to impaired absorption.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Various reports confirming this association have subsequently been published. However, to our knowledge (and a search on MEDLINE), no observational studies have been conducted in Spain comparing patients with type 2 diabetes treated and not treated with metformin.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">An observational, cross-sectional study was conducted on consecutive patients with type 2 diabetes mellitus on drug treatment seen at two internal medicine clinics of a first level hospital in the north of the province of Cáceres. Plasma levels of vitamin B<span class="elsevierStyleInf">12</span> were measured in all patients. Vitamin B<span class="elsevierStyleInf">12</span> deficiency was defined as levels less than 197<span class="elsevierStyleHsp" style=""></span>pg/mL (the lower limit of normal in our laboratory). Patients with vitamin B<span class="elsevierStyleInf">12</span> deficiency were asked about their dietary habits and antiparietal cell and anti-intrinsic factor antibodies were measured. An upper GI tract endoscopy was also performed to rule out atrophic chronic gastritis when it was considered indicated and with the patient's consent. PA was diagnosed based on plasma vitamin B<span class="elsevierStyleInf">12</span> levels less than 197<span class="elsevierStyleHsp" style=""></span>pg/mL, the presence of anti-intrinsic factor antibodies and/or atrophic chronic gastritis in gastric biopsies, and the response to treatment with vitamin B<span class="elsevierStyleInf">12</span> in patients with hematological or neurological evidence of PA.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using a Chi-square test, and a Fisher exact test when any of the expected values was less than 5, to compare proportions, and a Student's <span class="elsevierStyleItalic">t</span>-test for means comparison. A value of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 was considered statistically significant.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study sample consisted of 114 patients, of whom 5 (4.4%) were excluded due to PA having been diagnosed. The characteristics of patients treated and not treated with metformin are reported in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Among the patients treated with metformin, mean treatment time was 43.5 months (range 6–200 months) and mean dose 1779<span class="elsevierStyleHsp" style=""></span>mg/day (range 425–2550<span class="elsevierStyleHsp" style=""></span>mg/day). Patients treated with metformin had significantly lower plasma vitamin B<span class="elsevierStyleInf">12</span> levels (393.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>184.2 versus 509<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>176.4<span class="elsevierStyleHsp" style=""></span>pg/mL, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0008). Seven (8.6%) of the 81 patients treated with metformin and none of the 28 patients given metformin had plasma vitamin B<span class="elsevierStyleInf">12</span> levels less than 197<span class="elsevierStyleHsp" style=""></span>pg/mL. No patient with vitamin B<span class="elsevierStyleInf">12</span> deficiency (excluding those diagnosed with pernicious anemia) had macrocytic anemia, neuropathy, or cognitive impairment.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">No correlation was found between metformin dose and plasma vitamin B<span class="elsevierStyleInf">12</span> levels (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.02, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.45) or between treatment time with metformin and plasma vitamin B<span class="elsevierStyleInf">12</span> levels (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.15, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.78). Among the patients treated with metformin, there was no significant difference in plasma vitamin B<span class="elsevierStyleInf">12</span> levels between those taking and not taking a proton pump inhibitor (PPI) (409.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>205.3 versus 385.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>174.1<span class="elsevierStyleHsp" style=""></span>pg/mL, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.58).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">Metformin causes vitamin B<span class="elsevierStyleInf">12</span> malabsorption.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> The absorption of vitamin B<span class="elsevierStyleInf">12</span> bound to intrinsic factor produced from ileum is calcium-dependent. Calcium in ileal lumen enhances uptake of the vitamin B<span class="elsevierStyleInf">12</span>-intrinsic factor complex by the ileal cell receptor, and metformin impairs calcium availability at ileal level.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Various studies, including the current study, support the association of metformin therapy with decreased plasma levels of vitamin B<span class="elsevierStyleInf">12</span>. A study published in 1976 reported low plasma vitamin B<span class="elsevierStyleInf">12</span> levels in 5 (16.7%) out of 30 diabetic patients treated with metformin.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In another retrospective study, patients treated with metformin had significantly lower plasma vitamin B<span class="elsevierStyleInf">12</span> levels (496 versus 637<span class="elsevierStyleHsp" style=""></span>pg/mL).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In a large observational study, 5.8% of diabetic patients over 50 years of age treated with metformin for a mean of 5 years had vitamin B<span class="elsevierStyleInf">12</span> deficiency, as compared to 2.4% of diabetic patients not given metformin.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In a prospective study of patients with type 2 diabetes mellitus treated with insulin, 9.9% of patients given metformin at doses of 2,550<span class="elsevierStyleHsp" style=""></span>mg/day for longer than 4 years had vitamin B<span class="elsevierStyleInf">12</span> levels less than 150<span class="elsevierStyleHsp" style=""></span>pmol/L (200<span class="elsevierStyleHsp" style=""></span>pg/mL), as compared to 2.7% of patients who received placebo.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> These results may be considered similar to those of the present study.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The effect of metformin in decreasing plasma vitamin B<span class="elsevierStyleInf">12</span> levels is not transient and appears to increase with treatment duration.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,8,9</span></a> A progressive decrease over time (during more than 4 years of follow-up) in mean plasma vitamin B<span class="elsevierStyleInf">12</span> levels has been reported in patients treated with metformin.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,8</span></a> A case–control study showed an association between vitamin B<span class="elsevierStyleInf">12</span> deficiency and the dose and duration of metformin treatment.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> By contrast, our study found no correlation between metformin treatment dose and duration and plasma vitamin B<span class="elsevierStyleInf">12</span> levels. It should be noted, however, that short-term treatment with metformin already decreases vitamin B<span class="elsevierStyleInf">12</span> levels. In a 6-month study, treatment with metformin caused a mean 20<span class="elsevierStyleHsp" style=""></span>pg/mL reduction in vitamin B<span class="elsevierStyleInf">12</span> levels.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> An additional 16-week study also showed a 14% reduction in plasma vitamin B<span class="elsevierStyleInf">12</span> levels.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The use of PPIs has also been associated with vitamin B<span class="elsevierStyleInf">12</span> deficiency.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Acid secretion inhibition impairs vitamin B<span class="elsevierStyleInf">12</span> release from food.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> However, our study found no negative impact of treatment with PPIs on plasma vitamin B<span class="elsevierStyleInf">12</span> levels. This observation agrees with the findings in another study.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">All the patients in this study with vitamin B<span class="elsevierStyleInf">12</span> deficiency associated with metformin had so-called “asymptomatic” deficiency (defined as low plasma vitamin B<span class="elsevierStyleInf">12</span> levels with no associated macrocytic anemia, neuropathy, or cognitive impairment).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> However, this deficiency is not always asymptomatic. In a series of 10 patients with vitamin B<span class="elsevierStyleInf">12</span> deficiency associated with metformin, 9 patients had mild anemia and 3 had peripheral neuropathy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Isolated cases of patients with symptomatic vitamin B<span class="elsevierStyleInf">12</span> deficiency associated with metformin have also been reported.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> There is no agreement as to whether patients with “asymptomatic” vitamin B<span class="elsevierStyleInf">12</span> deficiency should be treated.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> There are signs of vitamin B<span class="elsevierStyleInf">12</span> deficiency, particularly neurological signs, which are difficult to diagnose and may become irreversible.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In addition, vitamin B<span class="elsevierStyleInf">12</span> deficiency is invariably associated with elevated homocysteine levels<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,11</span></a> and their potentially harmful consequences.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,17</span></a> On the other hand, one study did not show an improvement in cognitive function after vitamin B<span class="elsevierStyleInf">12</span> administration to elderly patients with mild vitamin B<span class="elsevierStyleInf">12</span> deficiency.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">An additional concept, functional vitamin B<span class="elsevierStyleInf">12</span> deficiency, is defined as the presence of normal vitamin B<span class="elsevierStyleInf">12</span> levels together with increased plasma levels of methylmalonic acid and is based on the fact that vitamin B<span class="elsevierStyleInf">12</span> deficiency invariably causes elevated methylmalonic acid levels.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19–21</span></a> Such a functional deficiency has been associated with neuropathy and anemia.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19–21</span></a> An increased frequency of neuropathy has recently been reported in patients with type 2 diabetes mellitus and this functional deficiency, as well as an improvement in neuropathy after the administration of vitamin B<span class="elsevierStyleInf">12</span> and the normalization of plasma levels of methylmalonic acid.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">There is no agreement regarding the convenience of regular measurements of plasma vitamin B<span class="elsevierStyleInf">12</span> levels in patients treated with metformin.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9,14,15,22</span></a> Controversy also exists concerning the management of patients with vitamin B<span class="elsevierStyleInf">12</span> deficiency associated with metformin, and some authors even suggest that metformin should be discontinued. In agreement with other authors,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,8</span></a> we think it is appropriate to regularly measure plasma vitamin B<span class="elsevierStyleInf">12</span> levels in patients treated with metformin, although other authors advise against such measurements.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Moreover, we think it is appropriate to continue treatment with metformin in patients with vitamin B<span class="elsevierStyleInf">12</span> deficiency and to treat such patients with oral or intramuscular vitamin B<span class="elsevierStyleInf">12</span> even if the deficiency is “asymptomatic”. In our experience (data not collected in the study) and that of other authors,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> plasma vitamin B<span class="elsevierStyleInf">12</span> levels easily normalized after the administration of oral or intramuscular vitamin B<span class="elsevierStyleInf">12</span>. This approach is based on the benefits of metformin for patients with type 2 diabetes mellitus and on the fact that treatment with vitamin B<span class="elsevierStyleInf">12</span> is simple, inexpensive, and safe and also has potential benefits.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Oral calcium supplements may reverse vitamin B<span class="elsevierStyleInf">12</span> malabsorption induced by metformin, and could be a treatment option.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres148832" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec136741" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres148833" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec136740" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-04-11" "fechaAceptado" => "2012-06-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec136741" "palabras" => array:4 [ 0 => "Cobalamin" 1 => "Diabetes mellitus" 2 => "Metformin" 3 => "Vitamin B<span class="elsevierStyleInf">12</span>" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec136740" "palabras" => array:4 [ 0 => "Cobalamina" 1 => "Diabetes mellitus" 2 => "Metformina" 3 => "Vitamina B<span class="elsevierStyleInf">12</span>" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To test vitamin B<span class="elsevierStyleInf">12</span> plasma levels in type 2 diabetic patients treated with metformin in our area.</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A cross-sectional, observational study of consecutive type 2 diabetic patients on drug treatment attending an internal medicine outpatient clinic.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">One hundred and nine patients (81 treated with metformin) were enrolled into the study. Mean time on metformin treatment was 43.5 months and mean drug dose was 1779<span class="elsevierStyleHsp" style=""></span>mg/day. Patients treated with metformin had significantly lower vitamin B<span class="elsevierStyleInf">12</span> plasma levels (393.5 vs 509<span class="elsevierStyleHsp" style=""></span>pg/mL, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0008). Seven (8.6%) of 81 patients treated with metformin and none of the 28 patients not treated with the drug had vitamin B<span class="elsevierStyleInf">12</span> plasma levels lower than 197<span class="elsevierStyleHsp" style=""></span>pg/mL. No correlation was found between vitamin B<span class="elsevierStyleInf">12</span> plasma levels and metformin treatment time or dosage.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In type 2 diabetic patients, treatment with metformin is associated to lower vitamin B<span class="elsevierStyleInf">12</span> plasma levels. Vitamin B<span class="elsevierStyleInf">12</span> deficiency associated with metformin is relatively common in our area.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudiar los niveles plasmáticos de vitamina B<span class="elsevierStyleInf">12</span> en pacientes diabéticos tipo 2 tratados con metformina en nuestro medio.</p> <span class="elsevierStyleSectionTitle">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional transversal de pacientes consecutivos con diabetes mellitus tipo 2 en tratamiento farmacológico atendidos en consulta de Medicina Interna.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 109 pacientes (81 en tratamiento con metformina). El tiempo medio en tratamiento con metformina fue 43,5 meses y la dosis media fue 1.779<span class="elsevierStyleHsp" style=""></span>mg/día. Los pacientes tratados con metformina tuvieron unas concentraciones plasmáticas de vitamina B<span class="elsevierStyleInf">12</span> significativamente menores (393,5 frente a 509 pg/ml, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,0008). Siete (8,6%) de 81 pacientes tratados con metformina y ninguno de los 28 no tratados con metformina tuvieron unas concentraciones plasmáticas inferiores a 197 pg/ml. No hubo correlación entre las concentraciones de vitamina B<span class="elsevierStyleInf">12</span> y el tiempo en tratamiento con metformina o la dosis de metformina.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En pacientes diabéticos tipo 2, el tratamiento con metformina se asocia a concentraciones plasmáticas de vitamina B<span class="elsevierStyleInf">12</span> más bajas. El déficit de vitamina B<span class="elsevierStyleInf">12</span> asociado a metformina es relativamente frecuente en nuestro medio.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Calvo Romero JM, Ramiro Lozano JM. Vitamina B<span class="elsevierStyleInf">12</span> en pacientes diabéticos tipo 2 en tratamiento con metformina. Endocrinol Nutr. 2012;59(8):487–90.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">HbA<span class="elsevierStyleInf">1c</span>: glycosylated hemoglobin; PPIs: proton pump inhibitors; BMI: body mass index; NS: no statistically significant (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>0.05).</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">With metformin (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Without metformin (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex (female) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 (69.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (57.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMI (kg/m<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment with PPIs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (57.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment with insulin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (21%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (39.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HbA<span class="elsevierStyleInf">1c</span> (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab242914.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients with and without metformin treatment.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An update on cobalamin deficiency in adults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Dali-Youcef" 1 => "E. Andrès" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/qjmed/hcn138" "Revista" => array:6 [ "tituloSerie" => "QJM" "fecha" => "2009" "volumen" => "102" "paginaInicial" => "17" "paginaFinal" => "28" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18990719" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin B-12 deficiency in the elderly: current dilemmas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.P. Stabler" 1 => "J. Lindenbaum" 2 => "R.H. Allen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Clin Nutr" "fecha" => "1997" "volumen" => "66" "paginaInicial" => "741" "paginaFinal" => "749" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9322547" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin-B12 status of patients on long-term metformin therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.H. Tomkin" 1 => "D.R. Hadden" 2 => "J.A. Weaver" 3 => "D.A. Montgomery" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "BMJ" "fecha" => "1971" "volumen" => "2" "paginaInicial" => "685" "paginaFinal" => "687" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20792936" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W.A. Bauman" 1 => "S. Shaw" 2 => "E. Jayatilleke" 3 => "A.M. Spungen" 4 => "V. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 18 | 3 | 21 |
| 2024 October | 141 | 11 | 152 |
| 2024 September | 173 | 12 | 185 |
| 2024 August | 124 | 10 | 134 |
| 2024 July | 140 | 13 | 153 |
| 2024 June | 176 | 19 | 195 |
| 2024 May | 217 | 10 | 227 |
| 2024 April | 181 | 13 | 194 |
| 2024 March | 242 | 30 | 272 |
| 2024 February | 301 | 15 | 316 |
| 2024 January | 382 | 31 | 413 |
| 2023 December | 273 | 24 | 297 |
| 2023 November | 389 | 27 | 416 |
| 2023 October | 300 | 47 | 347 |
| 2023 September | 235 | 14 | 249 |
| 2023 August | 232 | 21 | 253 |
| 2023 July | 190 | 29 | 219 |
| 2023 June | 166 | 25 | 191 |
| 2023 May | 315 | 37 | 352 |
| 2023 April | 174 | 24 | 198 |
| 2023 March | 177 | 29 | 206 |
| 2023 February | 103 | 18 | 121 |
| 2023 January | 101 | 13 | 114 |
| 2022 December | 120 | 14 | 134 |
| 2022 November | 112 | 19 | 131 |
| 2022 October | 95 | 18 | 113 |
| 2022 September | 88 | 13 | 101 |
| 2022 August | 109 | 21 | 130 |
| 2022 July | 93 | 14 | 107 |
| 2022 June | 90 | 26 | 116 |
| 2022 May | 131 | 34 | 165 |
| 2022 April | 113 | 20 | 133 |
| 2022 March | 131 | 28 | 159 |
| 2022 February | 116 | 21 | 137 |
| 2022 January | 119 | 33 | 152 |
| 2021 December | 130 | 36 | 166 |
| 2021 November | 151 | 35 | 186 |
| 2021 October | 173 | 23 | 196 |
| 2021 September | 129 | 24 | 153 |
| 2021 August | 153 | 22 | 175 |
| 2021 July | 86 | 20 | 106 |
| 2021 June | 138 | 29 | 167 |
| 2021 May | 129 | 16 | 145 |
| 2021 April | 372 | 119 | 491 |
| 2021 March | 328 | 31 | 359 |
| 2021 February | 202 | 35 | 237 |
| 2021 January | 159 | 19 | 178 |
| 2020 December | 128 | 25 | 153 |
| 2020 November | 85 | 14 | 99 |
| 2020 October | 50 | 21 | 71 |
| 2020 September | 37 | 6 | 43 |
| 2020 August | 40 | 14 | 54 |
| 2020 July | 37 | 13 | 50 |
| 2020 June | 30 | 11 | 41 |
| 2020 May | 52 | 11 | 63 |
| 2020 April | 42 | 11 | 53 |
| 2020 March | 62 | 7 | 69 |
| 2020 February | 48 | 6 | 54 |
| 2020 January | 58 | 15 | 73 |
| 2019 December | 44 | 10 | 54 |
| 2019 November | 35 | 12 | 47 |
| 2019 October | 27 | 3 | 30 |
| 2019 September | 42 | 16 | 58 |
| 2019 August | 31 | 7 | 38 |
| 2019 July | 25 | 6 | 31 |
| 2019 June | 45 | 21 | 66 |
| 2019 May | 167 | 15 | 182 |
| 2019 April | 58 | 6 | 64 |
| 2019 March | 24 | 5 | 29 |
| 2019 February | 21 | 3 | 24 |
| 2019 January | 16 | 1 | 17 |
| 2018 December | 18 | 5 | 23 |
| 2018 November | 20 | 11 | 31 |
| 2018 October | 11 | 3 | 14 |
| 2018 September | 16 | 4 | 20 |
| 2018 August | 15 | 1 | 16 |
| 2018 July | 10 | 2 | 12 |
| 2018 June | 10 | 2 | 12 |
| 2018 May | 14 | 4 | 18 |
| 2018 April | 8 | 1 | 9 |
| 2018 March | 17 | 2 | 19 |
| 2018 February | 6 | 1 | 7 |
| 2018 January | 14 | 5 | 19 |
| 2017 December | 13 | 3 | 16 |
| 2017 November | 9 | 6 | 15 |
| 2017 October | 13 | 2 | 15 |
| 2017 September | 12 | 8 | 20 |
| 2017 August | 17 | 5 | 22 |
| 2017 July | 23 | 4 | 27 |
| 2017 June | 23 | 22 | 45 |
| 2017 May | 14 | 8 | 22 |
| 2017 April | 32 | 3 | 35 |
| 2017 March | 36 | 9 | 45 |
| 2017 February | 36 | 5 | 41 |
| 2017 January | 12 | 1 | 13 |
| 2016 December | 29 | 11 | 40 |
| 2016 November | 27 | 11 | 38 |
| 2016 October | 26 | 10 | 36 |
| 2016 September | 24 | 19 | 43 |
| 2016 August | 14 | 67 | 81 |
| 2016 July | 19 | 2 | 21 |
| 2016 June | 18 | 11 | 29 |
| 2016 May | 24 | 17 | 41 |
| 2016 April | 20 | 5 | 25 |
| 2016 March | 18 | 16 | 34 |
| 2016 February | 22 | 11 | 33 |
| 2016 January | 23 | 12 | 35 |
| 2015 December | 21 | 16 | 37 |
| 2015 November | 22 | 19 | 41 |
| 2015 October | 33 | 24 | 57 |
| 2015 September | 28 | 15 | 43 |
| 2015 August | 12 | 18 | 30 |
| 2015 July | 22 | 6 | 28 |
| 2015 June | 12 | 2 | 14 |
| 2015 May | 17 | 17 | 34 |
| 2015 April | 34 | 11 | 45 |
| 2015 March | 15 | 17 | 32 |
| 2015 February | 15 | 17 | 32 |
| 2015 January | 40 | 7 | 47 |
| 2014 December | 58 | 14 | 72 |
| 2014 November | 24 | 1 | 25 |
| 2014 October | 33 | 7 | 40 |
| 2013 November | 1 | 0 | 1 |
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