Euglycaemic diabetic ketoacidosis in a 43-year-old woman with type 2 diabetes mellitus on SGLT-2 inhibitor (empagliflozin).

We report a case of euglycaemic diabetic ketoacidosis (EDKA) in a 43-year-old woman with type 2 diabetes mellitus who presented to the emergency department with problems of vomiting, cough, shortness of breath and generalised weakness after following a ketogenic diet for 2 weeks. Therapy with sodium glucose transport protein-2 empagliflozin had been started 2 months prior. Initial evaluation revealed high anion gap metabolic acidosis with blood glucose level of 169 mg/dL. Treatment for EDKA with fluid resuscitation, intravenous insulin and dextrose resolved her acidosis and symptoms in less than 24 hours. Empaglifozin was discontinued on discharge. This entity represents a diagnostic challenge since the differential diagnosis is broad with a potentially misleading clinical presentation that can result in delayed diagnosis and adverse outcomes including acute kidney injury, multiple electrolyte abnormalities, cerebral oedema, acute respiratory distress syndrome, shock and death.

SGLT2 Inhibitors in Diabetes Mellitus Treatment.

Type 2 Diabetes Mellitus (T2DM) is a chronic illness with high prevalence in Mexico, Latin- America, and the world and is associated to high morbidity, disability, and mortality rate, especially in developing countries. T2DM physiopathology is very complex; insulin resistance in the muscle, liver, and adipose tissue, a reduction in the production of incretins (mainly GLP-1) in the intestine, increased glucagon synthesis, an insufficient response of insulin generation, and increased glucose reabsorption in the kidney lead all together to an hyperglycemic state, which has been closely associated with the development of micro and macrovascular complications. Sodium Glucose Linked Transporter 2 inhibitors (SGLT2i) are the most recent therapeutic class available for treating T2DM. SGLT2i central effect is a glycosuric action, and they can reverse the deleterious effect of tubular reabsorption of glucose in the diabetic patient resulting in greater hyperglycemia. Because their mechanism of action is completely different to current drugs, they can be considered as monotherapy or in combination with any other oral or parenteral medication, including different types of insulin or its analogues. This therapeutic synergy accomplishes a greater percentage of patients achieving glycemic control goals.

Relevancia clínica de la selectividad de los inhibidores del cotransportador sodio-glucosa tipo 2 / Clinical relevance of the selectivity of sodium-glucose cotransporter-2 inhibitors

La selectividad es la propiedad de un farmaco para unirse de forma preferente a una estructura biologica.La mayor parte de los farmacos pueden unirse y estimular o inhibir mas de un sistema. Por ello es interesante que sean selectivos para la estructura sobre la que se pretende actuar y que con las dosis empleadas no ejerzan efectos sobre otras que pueden producir reacciones adversas. La selectividad se valora mediante experimentos in vitro sobre organos o celulas aislados. Si se pretende comparar farmacos, el experimento debe realizarse sobre el mismo tejido y con el mismo diseno. Aun asi, los datos obtenidos no se pueden extrapolar directamente a la clinica, por la influencia de las propiedades farmacocineticas, que son las que permiten que el farmaco llegue en concentracion adecuada al lugar de accion. En el caso de los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) se valora su capacidad para inhibir el SGLT2 renal sin modificar el SGLT1 intestinal, cuya inhibicion podria producir reacciones adversas digestivas. Se calcula la concentracion necesaria para inhibir cada uno de los transportadores y el cociente entre la que inhibe SGLT1 y la necesaria para inhibir SGLT2. Cuanto mayor sea el cociente, mayor sera la selectividad y menor el riesgo de reacciones adversas digestivas. Los 3 iSGLT2 recientemente introducidos en terapeutica son suficientemente selectivos sobre SGLT2 como para que no sean esperables efectos sobre SGLT1 intestinal. Para diferenciar a los componentes de este grupo puede ser mas interesante analizar sus propiedades farmacocinéticas que sus caracteristicas farmacodinamicas, como la selectividad (AU)

Selectivity is the property of a drug to preferentially bind to a biological structure. Most drugs can bind and stimulate or inhibit more than one system. Therefore, it is important that they are selective for the intended site and that the doses used do not have effects on other sites, which could provoke adverse reactions. Selectivity is assessed through in vitro experiments on organs or isolated cells. If the aim is to compare drugs, the experiment should be conducted in the same tissue and with the same design. Even so, the results cannot be directly extrapolated to clinical practice due to the influence of pharmacokinetic properties, which allow an adequate dose of the drug to reach the target site. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are able to inhibit renal SGLT2 without modifying intestinal SGLT1, whose inhibition could produce gastrointestinal adverse reactions. The concentration needed to inhibit each of the transporters is calculated, as well as the ratio between the concentration that inhibits SGLT1 and the concentration needed to inhibit SGLT2. The higher the ratio, the greater the selectivity and the lower the risk of gastrointestinal adverse reactions. The three SGLT2i recently introduced in the therapeutic arsenal are sufficiently selective for SGLT2 to make effects on intestinal SGLT1 unlikely. To differentiate the components of this therapeutic class, its pharmacokinetic properties should be analysed rather than its pharmacodynamic characteristics, such as selectivity (AU)

Perfil clínico de los pacientes con diabetes mellitus tipo 2 tratados con inhibidores del cotransportador sodio-glucosa tipo 2 y experiencia clínica real en España / Clinical profile of patients with type 2 diabetes mellitus treated with sodiumglucose cotransporter-2 inhibitors and experience in real-world clinical practice in Spain

El objetivo fundamental del tratamiento en la diabetes tipo 2 es el control global de los factores de riesgo cardiovascular. En casi la mitad de los diabéticos tipo 2 no se logra alcanzar el objetivo de control glucémico y en muchos menos el control del peso y la presión arterial, a pesar de todo el arsenal terapéutico que en la última década ha ido apareciendo para el tratamiento de esta enfermedad. Por otra parte, los antidiabéticos secretagogos y la insulina se asocian a un incremento ponderal y aumentan el riesgo de hipoglucemias. Los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) se han posicionado en las guías como una alternativa en el mismo escalón terapéutico que el resto de opciones tras el inicio con metformina. En este trabajo se revisa el perfil del paciente más adecuado para ser tratado con iSGLT2 sobre la base de su eficacia y seguridad demostrada en ensayos clínicos controlados. Teniendo en cuenta los posibles efectos secundarios propios del mecanismo de acción de este nuevo grupo terapéutico, se valora en qué pacientes de riesgo deben emplearse con precaución. Estas consideraciones acerca del perfil del paciente susceptible de ser tratado con iSGLT2 se contrastan con los resultados obtenidos en la práctica clínica diaria, tanto en estudios retrospectivos de otros países como en experiencias en práctica clínica real en España. Se presenta una selección de estudios realizados en diferentes centros con un seguimiento mínimo de 6 meses y se comparan con los resultados de los ensayos clínicos. Los iSGLT2 se utilizan en la práctica clínica en cualquier escalón terapéutico y se obtienen resultados de eficacia muy similares a los reportados en ensayos controlados, con una proporción algo más elevada de infecciones genitourinarias y una escasa tasa de abandonos. La mitad de los pacientes reportados son diabéticos insulinizados, a los que se añade una gliflozina, lo que demuestra la gran aceptación por parte de los clínicos de esta estrategia terapéutica. Los iSGLT2 resultan especialmente atractivos por su eficacia añadida en control del peso y presión arterial y la posibilidad de utilizarlos en asociación a otros antidiabéticos o en monoterapia en cualquier estadio evolutivo de la diabetes tipo 2 (AU)

The main aim of the treatment of type 2 diabetes is overall control of cardiovascular risk factors. Almost 50% of patients with type 2 diabetes do not achieve glycaemic targets, and a much higher percentage do not achieve weight and blood pressure targets, despite the therapeutic arsenal that has appeared in the last decade for the treatment of this disease. In addition, antidiabetic secretatogues and insulin are associated with weight gain and an increased risk of hyperglycaemic episodes. Clinical practice guidelines recommend sodium-glucose cotransporter-2 inhibitors (SGLT2i) as an alternative in the same therapeutic step as the other options after initiation of metformin therapy. The present study reviews the most appropriate patient profile for SGLT2i therapy, based on their safety and efficacy demonstrated in controlled clinical trials. The article discusses which patients are at risk of experiencing the possible secondary effects due to the mechanism of action of this new therapeutic class, in whom SGLT2i should be used with caution. These considerations on the profile of patients suitable for SGLT2i therapy are contrasted with the results obtained in daily clinical practice, both in retrospective studies from other countries and from real-world experiences in Spain. This article presents a selection of studies performed in distinct centres with a minimum follow-up of 6 months and compares their results with those from clinical trials. SGLT2i are used in clinical practice in any therapeutic step and the efficacy results are very similar to those reported by controlled clinical trials, with a slightly higher proportion of genitourinary infections and a low dropout rate. Half the reported patients are diabetics receiving insulin therapy plus a gliflozin, showing the wide uptake of this therapeutic strategy by clinicians. SGLT2i are especially attractive due to their additional effectiveness in weight and blood pressure control and the possibility of using them in association with other antidiabetic agents or in monotherapy in patients at any stage of type 2 diabetes (AU)

Pharmacotherapy in type 2 diabetes: a functional schema for drug classification.

With growing awareness that long-term hyperglycemia is directly implicated in the tissue damage characteristic of diabetes, there has been a corresponding increase in clinicians' willingness to employ intensive treatment to achieve euglycemia, which may require diabetes drugs in combination. The expanding array of drugs with different mechanisms of action calls for a clear method of classification to guide rational combination therapy. Contemporary and historical literature was surveyed to document changes in awareness of toxicity from hyperglycemia and consequent changes in treatment strategy. References were selected for clinical applicability and explanation of drug mechanisms of action, with the goal of proposing a useful schema for classification. Diabetes drugs may be classified in the following categories: insulin providers, which increase the supply of insulin through administration of exogenous human insulin or analogues or drugs that stimulate endogenous insulin secretion (sulfonylureas and meglitinides are direct insulin secretagogues, whereas glucagon- like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors act to increase the supply of insulin); insulin sensitizers (metformin, thiazolidinediones), which offset the effects of insulin resistance; and insulin-independent drugs, which work in the gut to impede intestinal absorption of glucose into the circulation (α-glucosidase inhibitors) or in the kidney to prevent renal reabsorption of glucose back into the circulation (sodium-glucose cotransporter 2 inhibitors, currently investigational). Awareness of these categories facilitates rational combinations of drugs with differing mechanisms of action to address hyperglycemia from separate directions, in accordance with current treatment guidelines.

Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight.

AIM: Dapagliflozin is a stable, competitive, reversible, and highly selective inhibitor of sodium-glucose co-transporter 2, the major transporter responsible for renal glucose reabsorption. With an insulin-independent mechanism of action, dapagliflozin is currently being developed for the treatment of type 2 diabetes mellitus (T2DM). This work aims to compare the efficacy of dapagliflozin, as measured by the change in hemoglobin A1c concentration (A1c) and body weight, and to determine the pharmacodynamic effects of dapagliflozin, as measured by urinary glucose excretion in early-stage and late-stage T2DM patient populations. METHODS: A total of 151 early-stage patients and 58 late-stage patients with T2DM randomly assigned 10 or 20 mg once daily (QD) dapagliflozin treatment or placebo for 12 weeks from two phase 2 studies were included in the analysis. A1c, body weight, and urinary glucose were compared between the two patient populations. RESULTS: Compared with the early-stage population, patients in the late-stage population had a longer duration of T2DM and higher baseline levels of A1c, body weight, fasting plasma glucose, and urinary glucose excretion. After 12 weeks of dapagliflozin treatment, A1c reduction, weight loss, and increased urinary glucose excretion from baseline were observed in both populations. Baseline A1c level impacted the A1c reduction after dapagliflozin treatment with a comparable effect in patients with early and late stage disease. Late-stage patients had greater reduction in body weight. There was no statistically significant difference in the amount of urinary glucose excretion between the early-stage and late-stage patients. CONCLUSIONS: Dapagliflozin treatment at 10 and 20 mg QD for 12 weeks resulted in significant improvement in glycaemic control and body weight reduction in both early-stage and late-stage patients with T2DM. The findings suggest that dapagliflozin could be a promising treatment option for a wide range of patients with T2DM.