Update on postprandial hyperglycaemia: the pathophysiology, prevalence, consequences and implications of treating diabetes. / Actualización sobre hiperglucemia posprandial: fisiopatología, prevalencia, consecuencias e implicaciones para el tratamiento de la diabetes.

To achieve appropriate glycaemic control, postprandial and baseline hyperglycaemia should be reduced. Various epidemiological studies have suggested an association between fluctuations in postprandial blood glucose and cardiovascular risk. However, studies of interventions performed to date have not shown that selective control of postprandial hyperglycaemia is associated with cardiovascular benefits. Accordingly, an appropriate combination of drugs that control both baseline and postprandial hyperglycaemia (individually based on each patient's characteristics) is the best strategy for achieving good glycaemic control. This review seeks to impart to clinicians the concept of postprandial hyperglycaemia, analysing its causes, how to measure it, its prevalence, its consequences and, ultimately, the available therapeutic strategies for the preferential control of the postprandial hyperglycaemia along with baseline hyperglycaemia.

Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included.

Diabetes screening by telecentric digital holographic microscopy.

Diabetes is currently the world's fastest growing chronic disease and it is caused by deficient production of insulin by the endocrine pancreas or by abnormal insulin action in peripheral tissues. This results in persistent hyperglycaemia that over time may produce chronic diabetic complications. Determination of glycated haemoglobin level is currently the gold standard method to evaluate and control sustained hyperglycaemia in diabetic people. This measurement is currently made by high-performance liquid chromatography, which is a complex chemical process that requires the extraction of blood from the antecubital vein. To reduce the complexity of that measurement, we propose a fully-optical technique that is based in the fact that there are changes in the optical properties of erythrocytes due to the presence of glucose-derived adducts in the haemoglobin molecule. To evaluate these changes, we propose to perform quantitative phase maps of erythrocytes by using telecentric digital holographic microscopy. Our experiments show that telecentric digital holographic microscopy allows detecting, almost in real time and from a single drop of blood, significant differences between erythrocytes of diabetic patients and healthy patients. Besides, our phase measurements are well correlated with the values of glycated haemoglobin and the blood glucose values.

Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice.

Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.

Taspoglutide, a once-weekly glucagon-like peptide 1 analogue, vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open-label randomized trial.

AIMS: To compare the efficacy and safety of once-weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. METHODS: This open-label, parallel-group, multi-centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA(1c) after 24 weeks. RESULTS: After 24 weeks, least-square mean changes from baseline in HbA(1c) in patients receiving taspoglutide 10 mg [-8 mmol/mol (se 1)] [-0.77% (se 0.05)] or taspoglutide 20 mg [-11 mmol/mol (se 1)] [-0.98% (se 0.05)] were non-inferior to insulin glargine [-9 mmol/mol (se 1)] [-0.84% (se 0.05)]; treatment difference of 0.07% (95% CI -0.06 to 0.21) and -0.14% (95% CI -0.28 to -0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. CONCLUSIONS: Compared with insulin glargine, taspoglutide provided non-inferior HbA(1c) reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.

Implementación de la estrategia basal plus en la práctica clínica / Basal plus strategy implementation in clinical practice

El tratamiento con insulina puede ser necesario en la diabetes tipo 2, dado que muchos pacientes, con el tiempo, no consiguen alcanzar o mantener los objetivos glucémicos para prevenir las complicaciones crónicas asociadas a la hiperglucemia sostenida. Inicialmente, la adición de insulina basal al tratamiento previo con agentes orales suele ser la pauta más habitual. Esta estrategia se basa en el control óptimo de la glucemia en ayunas. Sin embargo, un porcentaje significativo de pacientes no consiguen alcanzar o mantener el objetivo de HbA1c <=7%, debido a que presentan elevaciones excesivas de la glucemia posprandial. En consecuencia, el paso siguiente en la intensificación deltratamiento podría ser la adición de una dosis única de insulina prandial antes de la comida que provoca la mayor excursión posprandial (estrategia basal plus), manteniendo el tratamiento previo con insulina basal y agentes orales. Este régimen ha demostrado ser sencillo, eficaz y adecuado para un gran número de pacientes. Además, en caso necesario, facilita la introducción progresiva de inyecciones adicionales de insulina prandial hasta una estrategia bolo basal. En este artículo se resumen las recomendaciones de un grupo de trabajo multidisciplinar para una adecuada implementación de la estrategia basal plus en la práctica clínica habitual (AU)

Insulin treatment may be necessary in type 2 diabetes, because many patients are not able overthe time to achieve or maintain glycemic targets to prevent chronic complications associated to sustained hyperglycemia. Initially, addition of basal insulin to previous treatment with oral agentsis the most commonly used regimen. This strategy is based on optimal control of fasting plasma glucose. However, a significant proportion of patients does not achieve or maintain HbA1c target <=7%, because they show excessive postprandial glucose values. Therefore, the next step for intensification of treatment might be the addition of a single dose of prandial insulin before the main meal, which is associated with the greatest postprandial glucose excursion (basal plus strategy), maintaining previous treatment with basal insulin and oral agents. This regimen has demonstrated to be easy to use, effective and appropriate for many patients. Furthermore, if necessary, it makes easier progressive introduction of additional injections of prandial insulin until the basal bolus strategy. In this manuscript, recommendations from a multidisciplinary working group are summarized for an adequate implementation of the basal plus strategy in the routine clinical practice (AU)

Obstrucción intestinal aguda por bezoar en un paciente diabético tipo 2 con neuropatía / Acute intestinal obstruction caused by bezoar in a patient with type 2 diabetes and neuropathy

Un bezoar es una masa o concreción de material ingerido que se acumula en el estómago, desde donde puede pasar al resto del tracto intestinal. Son poco frecuentes, siendo el más común el fitobezoar. Éste se ha relacionado con la cirugía gástrica y con procesos que alteran la motilidad intestinal, como la gastroparesia diabética o la neuropatía alcohólica. En la mayoría de los casos se descubren de forma casual, y más raramente por la presencia de complicaciones asociadas. Presentamos el caso de un paciente con antecedentes de diabetes tipo 2 e ingesta crónica de alcohol, que presentó un cuadro obstructivo intestinal agudo causado por dos bezoares(AU)

A bezoar is a mass or concretion of ingested material which accumulates in the stomach, from it can progress into the rest of gastrointestinal tract. Bezoars are unusual, being the phytobezoar the most common. Phytobezoar shave been associated with gastric surgery and other pathologies that can alter intestinal motility, as diabetes gastroparesis or alcoholic neuropathy. In most cases they are found incidentally or, more rarely, they are discovered by associated complications. We report the case of a patient with type 2 diabetes and chronic alcoholism that presented an acute intestinal obstruction caused by two bezoars(AU)

Hiperglucemia posprandial y variabilidad glucémica: nuevos objetivos de control en la diabetes / Postprandial hyperglycemia and glycemic variability: new targets in diabetes management

La diabetes mellitus tipo 2 se caracteriza por la presencia de hiperglucemia deayuno y posprandial. Actualmente, la hemoglobina glucosilada (HbA1c) se considerael patrón de referencia en la evaluación del control glucémico en pacientescon diabetes. Los estudios de intervención en la diabetes mellitus tipo 1 y tipo 2demostraron de forma concluyente que reducir la HbA1c a menos del 7% previenela aparición/progresión de las complicaciones crónicas. Adicionalmente,otros estudios epidemiológicos y de intervención preliminares han demostradoque la hiperglucemia posprandial es un factor de riesgo independiente de enfermedadcardiovascular. La hiperglucemia crónica sostenida produce una glicaciónproteica excesiva, pero también los pacientes diabéticos presentan a diario fl uctuacionesagudas de la glucemia (variabilidad glucémica). Estas situaciones puedenactivar el estrés oxidativo y contribuir a la disfunción endotelial, que puededesempeñar también un papel en el desarrollo de las complicaciones diabéticas.De hecho, en los pacientes diabéticos, muchos factores de riesgo cardiovascularson modifi cados en el periodo posprandial, y están afectados directamente porlas oscilaciones agudas de la glucemia. Por tanto, reducir la hiperglucemia posprandialy la variabilidad glucémica se considera actualmente una prioridad terapéutica,y debe incluirse en la estrategia de prevención y tratamiento de la enfermedadcardiovascular en la diabetes(AU)

Type 2 diabetes is characterized by the presence of both fasting and postprandialhyperglycemia. Currently, glycated hemoglobin (HbA1c) is considered the«gold standard» for assessing glycemic control in patients with diabetes. Interventionalstudies in type 1 and type 2 diabetes have conclusively demonstratedthat reducing HbA1c to <7% prevent appearance and progression of chroniccomplications. Additionally, other epidemiological studies and preliminaryintervention studies have shown that postprandial hyperglycemia is an independentrisk factor for cardiovascular disease. Sustained chronic hyperglycemiaproduces excessive protein glycation, but people with diabetes suffersalso from daily acute glucose fluctuations, i.e. glucose variability. Acute changesof blood glucose may activate oxidative stress and contribute to endothelialdysfunction, which may also play a role in the development of diabeticcomplications. In fact, in diabetic subjects, most of the cardiovascular risk factorsare modified in the postprandial period, being affected directly by acuteoscillations of blood glucose. Therefore, reducing postprandial hyperglycemiaand glucose variability are now recognized as a treatment priority and shouldform part of the strategy for prevention and management of cardiovasculardisease in diabetes(AU)

Criterios profesionales sobre el papel de ezetimiba en el manejo clínico del paciente dislipémico en el ámbito de atención primaria / Professional criteria about the role of ezetimibe in clinical management of dyslipidemia in primary care

Introducción: A pesar de que ezetimiba fue introducida en España hace más de 5 años, existen todavía diferencias de criterio sobre el papel actual de este fármaco en el manejo de la dislipemia en atención primaria. Objetivos: Promover un consenso sobre el uso clínico de ezetimiba entre profesionales de atención primaria. Material y métodos: El estudio fue dividido en cuatro fases: 1) creación de un comité científico multidisciplinar (atención primaria, endocrinología y medicina interna) para revisión bibliográfica y formulación de un uestionario de 46 ítems sobre dislipemia y ezetimiba; 2) selección del panel de 91 médicos de atención primaria expertos en este campo; 3) encuesta Delphi en dos rondas, enviada por correo electrónico, y 4) sesión presencial final de discusión de resultados. Resultados: Participaron 87 profesionales que, en la primera ronda, lograron consensuar 34 de las 46 cuestiones analizadas. Tras la interacción del panel, el consenso aumentó hasta 42 ítems. En las 4 cuestiones restantes el consenso fue insuficiente, debido a las opiniones dispares o a la ausencia de criterio en la mayoría de los encuestados. Conclusiones: En este consenso, se presenta una amplia lista de criterios profesionales y/o recomendaciones para el uso de ezetimiba en atención primaria, que resumen la opinión profesional vigente entre los expertos de esta especialidad (AU)

Background: Since ezetimibe was first marketed in Spain more than 5 years ago, differences in criteria continue to exist about the current role played by ezetimibe in treating dyslipaemia in the primary care in Spain. Objectives: To develop consensus regarding the clinical use of ezetimibe in treating dyslipaemia in primary care. Methods: The study was divided into four stages: 1) constitution of a multidisciplinary scientific committee (primary care, endocrinology, internal medicine) for bibliographic review and formulation of a 46-items survey about dyslipaemia and ezetimibe; 2) constitution of a panel of 84 primary care professionals with expertise in this field; 3) Delphi survey in two rounds, sent by mail; and 4) a final discussion of the results in a face-to-face meeting. Results: Eighty-seven experts participated and, during the first round, reached a consensus in 34 out of 46 analysed questions. Following interaction by the panel, the consensus increased until 42 items. In the remaining 4 questions, insufficient consensus was obtained, due to opinion disparities existing among the professionals or to the absence of an established criterion for most of the experts. Conclusions: In this consensus, a long list of professional criteria and/or recommendations is included for the use of ezetimibe in primary care, summarising prevailing professional opinion of primary care experts (AU)

Síndrome de falta de reconocimiento de la hipoglucemia. Factores de riesgo y tratamiento / Hypoglycemia unawareness syndrome. Risk factors and treatment

La falta de reconocimiento de la hipoglucemia es un importante factorlimitante del tratamiento en la diabetes mellitus tipo 1 y tipo 2avanzada. Este problema, que ocurre hasta en un 25% de los pacientestratados con insulina, se caracteriza por una pérdida de lossíntomas autónomos de alarma antes de la aparición de la neuroglucopenia.La hipoglucemia inadvertida se asocia a un incremento deaproximadamente 7 veces el riesgo de sufrir hipoglucemias graves.Se han identifi cado diversos factores de riesgo para la hipoglucemiainadvertida, incluida la diabetes de larga duración, el control metabólicoestricto (valores bajos de HbA1c) y los episodios repetidos de hipoglucemia.La disminución de la respuesta contrarreguladora frentea la hipoglucemia es la causa principal de la hipoglucemia inadvertida.Evitar estrictamente las hipoglucemias restablece casi completamentesu percepción. En consecuencia, se han desarrollado diferentesestrategias terapéuticas para prevenir las hipoglucemias. Entreellas, el desdoblamiento de la insulina NPH nocturna, la infusión subcutáneacontinua de insulina, el uso preferente de los análogos deinsulina y, más recientemente, la monitorización continua de glucosa,han demostrado ser efectivas en la mayoría de casos(AU)

Hypoglycemia unawareness is a major limiting factor in the managementof type 1 and advanced type 2 diabetes. This common problem,which occurs in about 25% of patients treated with insulin, ischaracterized by loss of autonomic warning symptoms before developmentof neuroglycopenia. Hypoglycemia unawareness is also associatedwith ~7-fold increase in the risk to suffer severe hypoglycemia.Several risk factors for hypoglycemia unawareness have beenidentified, including long duration of diabetes, tight glycemic control(low HbA1c values), and repeated episodes of hypoglycemia. Reductionof counterregulatory hormone responses to hypoglycemia areprimarily responsible for hypoglycemia unawareness. Strict avoidingof hypoglycemia restores almost completely awareness of hypoglycemia.Therefore, several therapeutic strategies have been designedto prevent hypoglycemia. Among them, evening NPH insulin splitting,continuous subcutaneous insulin infusion, preferential use of insulinanalogues and, more recently, continuous glucose monitoring havebeen proved to be effective in most cases(AU)

Diagnóstico diferencial entre osteomielitis de pie y artropatía de Charcot aguda / Differential diagnosis between foot osteomyelitis and acute Charcot arthropathy

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Terapias basadas en el efecto incretina para el tratamiento de la diabetes tipo 2: revisión sistemática / Incretin-based therapies for the treatment of type 2 diabetes: a systematic review

Muchos pacientes con diabetes tipo 2 no logran alcanzar los objetivos glucémicos establecidos con los tratamientos disponibles, incluso cuando se usan en combinación, y desarrollan eventualmente complicaciones micro y macro vasculares. En consecuencia, se necesitan nuevos fármacos que traten con más eficacia la enfermedad, su progresión y sus complicaciones asociadas. Un área de emergente interés está centrada en las acciones de las hormonas con efecto incretinaGLP-1 (glucagon-like peptide-1; péptido 1 semejante al glucagón) y GIP (glucose-dependent insulinotropic polypeptide; polipéptidoinsulinotrópico dependiente de la glucosa). Estas hormonas aumentan la secreción de insulina estimulada por la ingesta e inhibenla secreción de glucagón. Además, tienen también efectos tróficos sobre la célula beta, incrementan la saciedad y disminuyen el apetito(GLP-1). Sobre la base de las acciones favorables de las incretinas, recientemente se han aprobado dos nuevas clases de fármacos para el tratamiento de la diabetes tipo 2: los análogos del GLP-1, estables y de larga duración (incretinmiméticos), y los inhibidores de la DPP-4 (dipeptidil peptidasa-4), la enzima responsable de la degradación rápida de las incretinas (potenciadores del efecto incretina). Estos fármacos consiguen reducciones sustanciales de la hemoglobina glucosilada, disminuyendo tanto la glucemia en ayunas como la glucemia pos prandial, y mejorando varios índices de la secreción de insulina. Los análogos de GLP-1, que deben administrarse por vía subcutánea, inducen pérdida de peso, pero tienen efectos adversos gastrointestinales relevantes. Los inhibidores de la DPP-4 son fármacos orales bien tolerados, sin efectos adversos asociados importantes, y neutros respecto al peso. Aunque se presentarán ambas clases de fármacos, esta revisión se centrará especialmente en los inhibidores de la DPP-4, los únicos fármacos disponibles hoy en España

Many patients with type 2 diabetes fail to achieve adequate glycaemic control with the available treatments, even when used in combination, and eventually develop micro- and macrovascular diabetic complications. Therefore, there is a need for new agents that more effectively treat the disease, its progression and its associated complications. One emerging area of interest is centered upon the actions of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones enhancemeal-induced insulin secretion and inhibit glucagon secretion. Additionally, they have also trophic effects on the beta-cell, increase satiety and diminish appetite (GLP-1). Based on the favorable actions of the incretin hormones, two new classes of agents have recently approved for therapy of type 2 diabetes: long-acting stable GLP-1-analogues (incretin mimetics) and inhibitors of dipeptidyl peptidase 4(DPP-4), the enzyme responsible for the rapid degradation of the incretin hormones (incretin enhancers). These agents achieve meaningful reduction of HbA1c, diminishing both fasting plasma glucose and postprandial hyperglycemia, and improving several indices of insulin secretion. GPL-1 analogues should be administered subcutaneously, induce weight reduction but have relevant gastrointestinal adverse effects.DPP-4 inhibitors are well tolerated oral drugs, without any significant associated adverse events, and weight neutral. Although both classes of agents will be discussed, this review will focus mainly onDPP-4 inhibitors, the only currently available drugs in Spain

Estrategias de insulinización en la diabetes mellitus tipo 2 / Insulin strategies in type 2 diabetes

La diabetes tipo 2 se caracteriza por una resistencia a la insulina y un deterioro progresivo de la función beta pancreática. Cuando dicha función se altera, muchos pacientes con diabetes mellitus tipo 2 necesitarán tratamiento con insulina. Diversos estudios clínicos han demostrado que un control estricto de la glucemia previene la aparición y progresión de las complicaciones microvasculares asociadas a la diabetes. La insulina es el fármaco existente más potente para conseguir un control óptimo de la glucemia solamente limitada por la hipoglucemia. Sin embargo, con frecuencia no se usa precozmente ni de forma lo suficientemente agresiva para alcanzar los objetivos terapéuticos necesarios en la prevención de las complicaciones crónicas de los pacientes. Recientemente, se han desarrollado nuevos análogos de insulina de acción prolongada y rápida que reproducen mejor el perfil fisiológico de la secreción de insulina en comparación con las insulinas humanas. Estas insulinas ofrecen mayor flexibilidady adaptabilidad, lo que propicia una mejora de la calidad de vida delos pacientes. La terapia con insulina debe iniciarse o intensificarse tan pronto como otros tratamientos no sean efectivos para alcanzarlas metas de control glucémico. En este manuscrito se revisan las diferentes estrategias disponibles para iniciar o intensificar el tratamiento con insulina en pacientes con diabetes tipo 2, como la adición de análogos de acción prolongada al tratamiento previo con hipoglucemiantes orales, las insulinas premezcladas o la terapia basal-bolus (AU)

Type 2 diabetes is characterized by insulin resistance and progressive beta-cell deterioration of pancreatic function. As beta-cell function declines, many patients with type 2 diabetes will require insulintherapy. Several clinical studies have shown that tight control of blood glucose levels prevents the development and progression of microvascular complications caused by diabetes. Insulin is the mostpotent drug currently available to achieve tight glycemic control only limited by hypoglycemia. However, it is not often used early or aggressively enough for patients to achieve the glycemic targets required to prevent chronic complications. Recently, new long-acting insulin analogues and rapid-acting insulin analogues were developed to better reproduce the physiological time-action profiles of insulin secretion compared with human insulin formulations. They offer more flexibility and convenience, there by improving patient’s quality of life. Insulin therapy should be initiated or intensify as soon as other diabetes therapies are no longer effective in achieving and sustaining glycemic targets. This article reviews the different treatment strategies available to initiate or intensify insulin therapy in people with type 2 diabetes such as addition of basal insulin analogues to priororal hypoglycemic agents, premixed insulin analogues or basal-bolustherapy (AU)

El futuro de la insulina inhalada tras la retirada de Exubera®: ®El fin del principio» / Future of inhaled insulin after Exubera ® withdrawal: ®The end of the beginning»

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