Letter to the Editor
Diabetic ketoacidosis associated to canagliflozin in type 2 diabetes
Cetoacidosis diabética asociada a canagliflozina en diabetes mellitus tipo 2
Silvia González Sanchidrián
, Juan Ramón Gómez-Martino Arroyo, Pedro Jesús Labrador Gómez
Corresponding author
Servicio de Nefrología, Hospital San Pedro de Alcántara, Complejo Hospitalario de Cáceres, Cáceres, Spain
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"documento" => "simple-article" "crossmark" => 1 "subdocumento" => "cor" "cita" => "Med Clin. 2017;148:192-3" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Family medicine in the training of the doctors of the future, and nowadays" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "192" "paginaFinal" => "193" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Medicina de familia en la formación del médico del futuro, y del presente" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Esteban González López, Maria Isabel García Lázaro, Angel Otero Puime" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Esteban" "apellidos" => "González López" ] 1 => array:2 [ "nombre" => "Maria Isabel" "apellidos" => "García Lázaro" ] 2 => array:2 [ "nombre" => "Angel" "apellidos" => "Otero Puime" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316306042" "doi" => "10.1016/j.medcli.2016.11.012" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316306042?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301298?idApp=UINPBA00004N" "url" => "/23870206/0000014800000004/v1_201703290102/S2387020617301298/v1_201703290102/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Diabetic ketoacidosis associated to canagliflozin in type 2 diabetes" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "e19" "paginaFinal" => "e20" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Silvia González Sanchidrián, Juan Ramón Gómez-Martino Arroyo, Pedro Jesús Labrador Gómez" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Silvia" "apellidos" => "González Sanchidrián" "email" => array:1 [ 0 => "silvia_goz@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Juan Ramón" "apellidos" => "Gómez-Martino Arroyo" ] 2 => array:2 [ "nombre" => "Pedro Jesús" "apellidos" => "Labrador Gómez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Nefrología, Hospital San Pedro de Alcántara, Complejo Hospitalario de Cáceres, Cáceres, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cetoacidosis diabética asociada a canagliflozina en diabetes mellitus tipo 2" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In May 2015, the US Food and Drug Administration, and later, its European and Spanish counterparts, warned of the risk of diabetic ketoacidosis (DKA) associated with the use of canagliflozin, dapagliflozin and empagliflozina.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Sodium-glucose cotransporter-2 inhibitors (SGLT2-I) are oral antidiabetic drugs (OAD) indicated in the treatment of diabetes mellitus (DM) 2, alone or in combination with insulin or other hypoglycaemic drugs.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">We present a case of DKA associated with canagliflozin in a 39 year-old man diagnosed with type 2 DM from 29, with a history of obesity, hypertriglyceridemia, smoking and poor metabolic control (glycosylated haemoglobin [HbA1c] 12%), without associated vascular complications. The patient had been treated with insulin, which suspended due to poor tolerance, and was currently in treatment with exenatide 2<span class="elsevierStyleHsp" style=""></span>mg/week and canagliflozin 100<span class="elsevierStyleHsp" style=""></span>mg/day. A week after the start of treatment with canagliflozin the patient came to the emergency room due to general malaise, fatigue and vomiting. He was conscious and oriented, afebrile, normally hydrated and well perfused but with significant malaise, tachycardia and tachypnea, with BP 143/92<span class="elsevierStyleHsp" style=""></span>mmHg. Neurological examination was normal. Blood tests showed glycaemia 252<span class="elsevierStyleHsp" style=""></span>mg/dl, severe metabolic acidosis (pH 6.98, <span class="elsevierStyleItalic">p</span>CO<span class="elsevierStyleInf">2</span> 28<span class="elsevierStyleHsp" style=""></span>mmHg, HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">−</span> 6.6<span class="elsevierStyleHsp" style=""></span>mEq/l), lactate<span class="elsevierStyleHsp" style=""></span>1.9<span class="elsevierStyleHsp" style=""></span>mmol/l and elevated anion gap (40<span class="elsevierStyleHsp" style=""></span>mEq/l); urine glucose >1000<span class="elsevierStyleHsp" style=""></span>mg/dl, impaired kidney function (urea 34<span class="elsevierStyleHsp" style=""></span>mg/dl and creatinine 1.22<span class="elsevierStyleHsp" style=""></span>mg/dl) and mild hyponatremia (132<span class="elsevierStyleHsp" style=""></span>mmol/l) with normal serum potassium. In the blood count, he showed mild leukocytosis (13,900 leukocytes, 85% neutrophils) without elevated acute phase reactants or signs of infection. Liver function tests and amylase and lipase levels were within the normal range.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Suspecting severe DKA,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> intensive fluid therapy, bicarbonate infusion and intravenous insulin therapy was initiated. The patient denied use of toxic substances and osmole hiatus <20<span class="elsevierStyleHsp" style=""></span>mOsm/l reasonably ruled out a metabolic acidosis secondary to alcohol poisoning. C-peptide levels were normal (2<span class="elsevierStyleHsp" style=""></span>ng/ml). Positive ketonuria (80<span class="elsevierStyleHsp" style=""></span>mg/dl) and ketonemia (β hydroxybutyrate 6.5<span class="elsevierStyleHsp" style=""></span>mmol/l) supported the diagnosis of DKA.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The patient required hospitalization. Hyperglycaemia and ketonemia were quickly corrected; metabolic acidosis persisted, but was corrected within the first 48<span class="elsevierStyleHsp" style=""></span>h. The patient improved and was discharged at 72<span class="elsevierStyleHsp" style=""></span>h with insulin treatment; OAD treatment was discontinued. Immunologic study was performed and the antibodies were negative.</p><p id="par0035" class="elsevierStylePara elsevierViewall">SGLT2-I act in the kidney on the SGLT2 cotransporter, responsible for most glucose reabsorption in the renal tubules, so its inhibition increases urinary glucose excretion and reduces plasma concentrations.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Due to its mechanism of action, the most common side effects are urinary tract infections and genital fungal infections, osmotic diuresis and volume depletion.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> However, the most serious side effect is DKA.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3–5</span></a> Most cases have occurred in diabetics treated with insufficient insulin dose, latent autoimmune diabetes in adults (LADA) or DM type 1, although the European Medicines Agency reported 101 cases of DKA in patients with DM type 2.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> The incidence reported by Peters et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> was 5.1–9.4% in DM type 1 treated with insulin and canagliflozin, while the one reported by Erondu et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> was 0.07% in DM type 2.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The kidney plays a key role in the regulation of blood glucose and ketone bodies in the body,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> but the exact mechanisms by which these OAD induce DKA are still unknown. DKA induced by SGLT2-I usually occurs with low glucose levels (<250<span class="elsevierStyleHsp" style=""></span>mg/dl) due to increased renal losses caused by these drugs, with the decrease of available glucose as an energy substrate being the main causal mechanism. Decreased renal elimination of ketone bodies by tubular reabsorption is also involved in the genesis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Precipitating factors are basically metabolic stress situations, dehydration, alcohol consumption or low-carbohydrate diets.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">DKA induced by SGLT2-I is a rare but serious complication that can go unnoticed due to its presentation (with non-excessively high blood glucose levels). If the condition is suspected, ketonemia determination is recommended for proper diagnosis and treatment.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> The patient should also be informed about risk situations that may precipitate the condition, requiring a temporary discontinuation of treatment.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: González Sanchidrián S, Gómez-Martino Arroyo JR, Labrador Gómez PJ. Cetoacidosis diabética asociada a canagliflozina en diabetes mellitus tipo 2. Med Clin (Barc). 2017;148:e19–e20.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Food and Drug Administration. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too mucha cid in the blood [online]; 2015. Available from: <a href="http://www.fda.gov/Drugs/DrugsSafety/ucm446845.htm">http://www.fda.gov/Drugs/DrugsSafety/ucm446845.htm</a> [accessed 19.04.15]" ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SGLT-2 inhibitors and their potential in the treatment of diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R.F. 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Meininger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc15-1251" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2015" "volumen" => "38" "paginaInicial" => "1680" "paginaFinal" => "1686" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26203064" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000014800000004/v1_201703290102/S2387020617300189/v1_201703290102/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014800000004/v1_201703290102/S2387020617300189/v1_201703290102/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617300189?idApp=UINPBA00004N" ]
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