Nueva generación de insulinas: glargina U300: Resumen de evidencia clínica / New generation of insulins: glargine U300. Summary of clinical evidence

La diabetes mellitus tipo 2 tiene evolución crónica y progresiva, prevalencia creciente y aún es diagnosticada tardíamente. Esto conlleva mayor incidencia de complicaciones crónicas, con incremento de costos en salud. Existe retraso en el inicio de insulinoterapia por causas relacionadas tanto al paciente como al médico. A pesar de los avances en su tratamiento, una baja proporción de enfermos logra control glucémico adecuado. La alta prevalencia de hipoglucemia en pacientes insulino-tratados, impulsó el desarrollo de una nueva generación de insulinas basales de acción prolongada, mayor estabilidad con menor variabilidad y riesgo de hipoglucemias. El programa EDITION evaluó la eficacia y seguridad de glargina U300 vs. glargina U100 en pacientes con diabetes tipo 1 y 2, en distintas etapas de la enfermedad. Glargina U300 es una nueva formulación de insulina glargina con perfil farmacocinético y farmacodinámico más estable y prolongado que glargina U100. Glargina U300 demostró eficacia y tolerabilidad comparable a glargina U100, con descenso significativo del riesgo de hipoglucemias nocturnas y en 24 horas, aportando mayor flexibilidad en el horario de inyección, con una ventana de 6 horas. Además, no se observó mayor aumento de peso que con glargina U100. El estudio Bright (2018) comparó glargina U300 vs. degludec U100, demostrando mayor beneficio en relación al riesgo de hipoglucemia con Gla-300 durante el período de titulación. Gla-300 es una insulina basal de última generación, disponible para mejorar el control metabólico, con menor riesgo de hipoglucemia.

Type 2 diabetes is a chronic, progressive disease with increasing prevalence and still late diagnostic. This leads to an increase in the incidence of chronic complications, with signifi cantly increasing health costs. There is also a delay in the onset of insulin therapy in patients with type 2 diabetes for causes related to both patients and physicians. Despite advances in treatment, a low proportion of patients achieve adequate glycemic control. The high hypoglycemia prevalence, consequence of insulin, has led to the development of a new generation long-acting basal insulins to achieve a more stable and prolonged action profile, reducing the variability and risk of hypoglycemia. The EDITION program evaluated the efficacy and safety of glargine U300 compared to glargine U100 in patients with type 1 and 2 diabetes at different stages of the disease. Gla-300 is a new formulation of insulin glargine which has a more stable and prolonged pharmacokinetic and pharmacodynamic profile. Gla-300 demonstrated efficacy and tolerability comparable to glargine U100, with a significant decrease in the risk of hypoglycemia, at night and in 24 hours, providing greater flexibility in the injection schedule, with a window of 6 hours. No increase in weight was observed compared to glargine U100. Bright study (2018) compared glargine U300 vs. degludec U100, demonstrating greater benefit in relation to the risk of hypoglycemia with Gla-300 during titration period. Gla-300 is a last-generation basal insulin, available to improve metabolic control, with a lower risk of hypoglycemia.

Insulinización en la diabetes mellitus tipo 2: Alternativas de intensificación / Insulinization in type 2 diabetes mellitus. Intensification options

La diabetes mellitus se asocia con complicaciones vasculares y elevadas tasas de morbimortalidad. La terapia oportuna con insulina y su intensificación cuando es necesaria, representan estrategias apropiadas para evitar o retardar la aparición de dichas complicaciones. Sin embargo, la incidencia de hipoglucemia y las dificultades en la adherencia al tratamiento representan barreras para alcanzar el éxito terapéutico. Las nuevas combinaciones de análogos de insulina constituyen tratamientos que presentarían ventajas farmacocinéticas y farmacodinámicas, logrando beneficios clínicos tales como un mejor control metabólico, la disminución de eventos hipoglucémicos y, por su simplicidad, potencialmente una mayor adherencia al tratamiento.

Diabetes mellitus is associated with vascular complications and high rates of morbidity and mortality. Timely insulin therapy, intensified when necessary, represent appropriate measures to prevent or delay the onset of complications. However, the incidence of hypoglycemia and difficulties in treatment adherence represent barriers to achieve therapeutic success. Premixes analogs and, specially, combinations of insulin analogues are associated with pharmacokinetic and pharmacodynamic advantages, that translate into clinical benefits such as improved metabolic control, decreased hypoglycemic events and, for their simplicity, potentially greater adherence.

Adherencia terapéutica y flexibilidad en el uso de las insulinas basales

Desde 1921, los beneficios alcanzados por las investigaciones sobre insulinoterapia han sido constantes. Sin embargo, el temor a las hipoglucemias y la rigidez horaria para administrar la insulina aún interfieren sobre la adherencia al tratamiento, que es esencial para lograr un buen control de la glucemia y minimizar las complicaciones en los pacientes con diabetes. En este contexto, se analiza la posibilidad de utilizar un análogo de insulina ultra-lento (degludec) que posee un perfil farmacocinético prolongado y predecible por más de 24 horas. En ensayos clínicos demostró que, al administrarlo en un esquema de dosis flexible mantiene un buen control de la glucemia, sin que aumente el riesgo de hipoglucemias. Si bien en la práctica clínica es aconsejable seguir un plan establecido, la posibilidad de flexibilizar el horario en la aplicación diaria del análogo ultra-lento en caso de ser necesario, podría mejorar la adherencia en pacientes con una vida social y laboral activa y poco previsible.

Since 1921, the benefits achieved by insulin therapy research have been constant. However, the fear of a hypoglycemia incidence and rigid time schedules of insulin therapy still interfere with treatment adherence, which is essential to achieve optimal glycemic control and minimize complications in diabetic patients. The possibility of using an ultra long-acting insulin analogue (degludec), which has an extensive and predictable pharmacokinetic profile over 24 hours, is analyzed in this context. Clinical trials have shown that this ultra long-acting insulin analogue administered in a flexible dosage treatment, reached a good glycaemic control with no increase on hypoglycemia risk. Although to follow a predefined plan in clinical practice is recommended, the possibility of flexibility in day to day dosage timing of this specific insulin analogue on requirement, could improve adherence in patients with a non-predictable and active social life and workday.

Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2 / Exenatide trials for the treatment of type 2 diabetes

La diabetes mellitus tipo 2 es una enfermedad metabólica crónica, frecuente y progresiva, responsable del 90% de los casos de diabetes a nivel mundial. Aproximadamente el 60% de los individuos que padecen este desorden no alcanzan niveles óptimos de hemoglobina glicosilada, a pesar de la disponibilidad de numerosas alternativas terapéuticas. Los dos objetivos más importantes a cumplir en el manejo actual de la diabetes tipo 2 son la capacidad de los agentes antidiabéticos de exhibir eficacia prolongada y la capacidad de preservar la función de las células beta pancreáticas. El efecto incretina se encuentra reducido en pacientes con diabetes tipo 2. Exenatida pertenece a un nuevo grupo de drogas antidiabéticas que mejoran el control de la glucemia en estos pacientes a través de mecanismos fisiológicos glucorregulatorios que mejoran el efecto incretina. Los ensayos clínicos fase III con exenatida demostraron una reducción media de aproximadamente el 1% en los valores de hemoglobina glicosilada. Los datos a largo plazo de estudios de extensión no controlados indican una mejoría sostenida en los niveles de hemoglobina glicosilada y una reducción progresiva del peso luego de 3 años de tratamiento con esta droga. La droga es generalmente bien tolerada y los efectos adversos más frecuentes son los gastrointestinales, con una intensidad leve a moderada. El objetivo de esta revisión es analizar la evidencia publicada hasta la fecha sobre la eficacia y tolerabilidad del tratamiento con exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

The Mechanism of Action of the Oral Anti-Diabetic Drugs: a Review of Recent Literature

Type 2 diabetes mellitus (DM) is a disorder that is placing an increasing burden on health service delivery worldwide. Consequently; it has become increasingly important that physicians who treat such patients have a good knowledge of antidiabetic drugs that are currently available or will come onto the market. This article presents an overview of all the major drug classes as well as some information on pharmacokinetics; pharmacodynamics; side-effect profiles and indications for use

Estudo comparativo da biodisponibilidade relativa de duas formulações de glimepirida em voluntários sadios de ambos os sexos após administração de uma dose única de um comprimido de 4 mg / Comparison study of two glimepiride formulations bioavailability in healthy volunteers of both sexes after a single dose administration

OBJETIVO: Comparar a biodisponibilidade de duas formulações de glimepirida em 26 voluntários sadios de ambos os sexos. MATERIAL E MÉTODOS: O estudo foi aberto, cruzado e randomizado com dois períodos e wash out de 14 dias. As amostras foram obtidas em um intervalo de 48 horas. As concentrações de glimepirida foram analisadas por HPLC MS/MS. Das curvas de concentração de glimepirida no plasma versus tempo, foram obtidos os seguintes parâmetros farmacocinéticos: ASC(0-t), ASC(0-∞), Cmax, Ke, Tmax e T1/2. RESULTADOS: A razão entre as média geométricas de Glimepirida/Amaryl® 4 mg foi de 102,35 por cento para ASC(0-t); 102,35 por cento para ASC(0-∞) e 99,31 por cento para Cmax. Os intervalos de confiança de 90 por cento (IC 90 por cento) foram de 92,62-109,55 por cento; 95,62-109,55 por cento e 88,60-111,32 por cento, respectivamente. CONCLUSÃO: Como o IC 90 por cento para Cmax, ASC(0-t) e ASC(0-∞) estava dentro do intervalo de 80-125 por cento, concluiu-se que ambas as formulações foram bioequivalentes de acordo com o grau e a extensão de sua absorção.

OBJECTIVE: To compare the bioavailability of two glimepiride 4-mg tablet formulation in 26 healthy volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with randomized two-period crossover design and a 14-day washout period. Samples were obtained over a 48-hour interval. Glimepiride concentrations were analyzed by LC-MS-MS. From the glimepiride plasma concentration versus time curves the following pharmacokinetic parameters were obtained: AUC(0-last), AUC(0-t), AUC(0-∞), Ke, T1/2, Cmax, and Tmax. RESULTS: Geometric mean of Glimepirida/Amaryl® 4 mg was 102.35 percent for AUC(0-t), 102.35 percent for AUC(0-∞) and 99.31 percent for Cmax. The 90 percent CI was 92.62-109.55 percent; 95.62-109.55 percent e 88.60-111.32 percent, respectively. CONCLUSION: Since the 90 percent CI for both Cmax, AUC(0-t), and AUC(0-∞) were within the interval of 80-125 percent, it was concluded that both formulations were bioequivalent, according to both the rate and extent of absorption.

Comparative study of princeps drugs dissolution of metformin commercialied in African countries

This study is presented to raise the awareness concerning the problems of the quality of princeps drugs used in developing countries. Its goal is to show that a drug is the result of a complex balance between a number of parameters and that, for the same active principle, the therapeutic effectiveness is conditioned by the pharmacotechnic characteristics, by the formulation in its galenic form and by manufacturing conditions. The comparison of the in vitro release of metformine from princeps products originating from different countries reveals pharmacotechnic differences: a delayed dissolution suggests a risk of reduction in effectiveness and an early dissolution a risk of overdose. Thus, the dissolution test applied to generic drugs could be of interest in the comparison between different princeps of a same active principle

Efeito do extrato bruto hidroalcoólico e de frações de folhas da Averrhoa carambola L. (Oxalidaceae) no metabolismo glicêmico de ratos Wistar / Effect of Hydroalcoholic extract and fractions of Averrhoa carambola L. (Oxalidaceae) leaves on the glycemic metabolism of Wistar rats

As folhas de carambola (Averrhoa carambola L.) são utilizadas na fabricação do fitoterápico Glico-Vitae®, indicado no tratamento do diabetes melittus tipo 2. Em nossos estudos, ratos machos Wistar que receberam, por via intragástrica, o extrato bruto liofilizado (EC) e as frações de EC (20 mg/kg), durante duas semanas, apresentaram redução da glicemia. Mas, diferentemente da insulina, o EC e suas frações não estimularam a síntese de glicogênio e a produção de lactato em músculo sóleo isolado. Da fração mais ativa, empregando métodos espectroscópicos de EM, RMN1H e RMN13C, foram isoladas três frações semipurificadas majoritárias e, por comparação com os dados da literatura, foram identificadas como misturas complexas de açúcares

Avaliação das atividades hipoglicemiante e antihiperglicemiante do extrato hidroalcóolico das folhas da Averrhoa carambola L. (Oxalidaceae) em modelos experimentais de hiperglicemia / Evaluation of hypoglycemic and antihyperglycemic activities in hydroethanolic extract of Averrhoa carambola L. (Oxalidaceae) in experimental models of hyperglycemia

As atividades hipoglicemiante e antihiperglicemiante do extrato hidroalcóolico obtido das folhas da Averrhoa carambola L. (Oxalidaceae) foram avaliadas em ratos, utilizandose diferentes modelos experimentais de hiperglicemia: diabetes tipo 1 induzido por aloxana, intolerância à glicose e resistência aguda à insulina induzidas pela dexametasona e resistência crônica à insulina em modelo de obesidade induzida pelo monoglutamato de sódio. O extrato hidroalcóolico da Averrhoa carambola, na dose de 800 mg/Kg de peso corporal, não apresentou atividades hipoglicemiantes e antihiperglicemiantes nos modelos de hiperglicemia testados

Fatores hepatotróficos e regeneraçäo hepática. Parte I: o papel dos hormônios / Hepatotrophic factors and liver regeneration. Part I: the role of hormones

No complexo processo de proliferaçäo celular, os hormônios agem de diferentes maneiras ao atingirem seus receptores nos tecidos-alvo. Os principais fatores ligados ao crescimento hepático säo HGF, TGF-alpha, IL-6, TNF-alpha, norepinefrina, EGF e insulina. O GH estimula tanto o fígado a produzir fatores de crescimento, como a expressäo genética do HGF e a síntese de DNA. Hormônios tireoideanos aumentam a capacidade proliferativa dos hepatócitos. A insulina age sinergicamente com GH e glucagon. Näo tem potencial mitogênico primário mas intensifica o estímulo regenerativo iniciado pela epinefrina e norepinefrina. Esta amplifica os sinais mitogênicos do EGF e HGF, induz a secreçäo de EGF e antagoniza os efeitos inibitórios do TGF-beta 1. O glucagon isoladamente näo produz efeitos mas provavelmente participa na síntese de DNA e da resposta homeostásica pela qual a glicemia é mantida estável durante a regeneraçäo. Também há indícios de açäo hepatotrófica da gastrina.

Tratamento oral do Diabetes Mellitus: uma nova categoria de antidiabético oral / Diabetes Mellitus oral treatment: a new group of oral antidiabetics

O diabete mellitus é uma patologia de evolução contínua, com conseqüências desastrosas, devido à micro e à macroangiopatia. Diferentes grupos de medicamentos orais, com ações em regiões variadas, procuram minimizar as lesões e retardá-las ao máximo. Infelizmente ainda não temos um grupo de medicamentos que se aproxime do ideal - o qual pudesse atuar retardando tanto quanto possível as complicações crônicas. Neste sentido apresentamos um grupo de substâncias que participam em um mesmo produto e que, devido às suas ações em diferentes regiões do corpo, provavelmente poderão modificar a história evolutiva desta patologia

Pharmacokinetic study of niosome encapsulated insulin.

Pharmacokinetic profile and hypoglycemic effect, after intraperitoneal injection of insulin and insulin encapsulated in niosomes were determined in diabetic rats. Niosomes (non-ionic surfactant vesicles) of different doses and different lipid compositions were prepared by lipid layer hydration method. Plasma samples were collected at specified time intervals and plasma concentration of insulin was determined by HPLC. Blood glucose level was estimated spectrophotometrically using commercial glucose assay kit. In vitro release and pharmacokinetic profile of niosomal formulation and free insulin were evaluated. Though there was a slight delay in the in vitro drug release due to cholesterol content in the niosomes, there was no difference between the two preparations when plasma levels were compared in vivo. Niosomes significantly reduced the blood glucose level in diabetic rats. Fall in blood glucose level was almost 92% of initial value. In case of the niosomal form the half-life of insulin was prolonged by 4 -5 hr in contrast to 2 hr for free drug. Niosomes maintained the plasma insulin level up to 12 hr, but free drug was cleared quickly. The area under the plasma concentration-time curve for niosomal forms was, 26.07 degrees +/- 0.99 mIU. hr/ml and for free insulin was 11.722 +/- 1.00 mIU. hr/ml. More than 80% of the drug was successfully encapsulated to give a formulation with sustained release characteristics. Entrapment efficiency increased with increasing lipid concentration and decreased with increasing drug concentration. The results showed that insulin entrapped in niosomes prolongs the existence of drug in the body therefore increasing its therapeutic value.

Insulin analogues and management of diabetes mellitus.

The introduction of insulin analogues, of which insulin lispro is the prototype, marks a very important milestone in the management of patients with diabetes mellitus. It differs from regular human insulin in its quicker onset and shorter duration of action. In various clinical trials, insulin lispro was found to be superior to regular human insulin in controlling postprandial hyperglycemia without increasing the risk of hypoglycemia. It improved the quality of life of diabetic patients by providing more flexibility to meal plans. Recently, another short acting insulin analogue called insulin aspart has been tried in clinical studies with benefits similar to insulin lispro. The turn of the millennium is now witnessing the development of long acting insulin analogues like insulin glargine, which can provide continuous low-level basal insulin concentrations similar to natural settings. In this review, we discuss the potential of insulin analogues in the modern management of diabetes with emphasis on insulin lispro.