RESUMEN
AIMS: To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis. METHODS: A total of 1499 participants from AWARD-1, AWARD-5, AWARD-8 and AWARD-9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non-alcoholic fatty liver/non-alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma-glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c , fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non-alcoholic fatty liver/non-alcoholic steatohepatitis subgroup. RESULTS: In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l). CONCLUSIONS: Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Proteínas Recombinantes de Fusión/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Diabetes Mellitus Tipo 2/complicaciones , Regulación hacia Abajo/efectos de los fármacos , Femenino , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/enzimología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Proteínas Recombinantes de Fusión/farmacología , Estudios Retrospectivos , Adulto Joven , gamma-Glutamiltransferasa/sangreRESUMEN
This substudy of the AWARD-3 trial evaluated the effects of the once-weekly glucagon-like peptide-1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C-peptide and glucagon levels were measured up to 3 h post-meal. ß-cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUCglucose (0-3 h)] were observed among all groups. ß-cell function [AUCinsulin /AUCglucose (0-3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and ß-cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing ß-cell function, while metformin exerts a greater effect on insulin sensitivity.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Resistencia a la Insulina , Metformina/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Anciano , Área Bajo la Curva , Glucemia/metabolismo , Péptido C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ayuno , Femenino , Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/uso terapéutico , Hemoglobina Glucada/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Periodo Posprandial , Resultado del TratamientoRESUMEN
Therapeutic administration of peptides may result in anti-drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment-emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA-positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non-GLP-1 comparators, N = 1141). Treatment-emergent dulaglutide ADAs were detected using a solid-phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell-based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide-treated patients (1.6% of the population) tested ADA-positive versus eight (0.7%) from the non-GLP-1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide-neutralizing ADAs, 36 (0.9%) had native-sequence GLP-1 (nsGLP-1) cross-reactive ADAs and four (0.1%) had nsGLP-1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA-positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control.
Asunto(s)
Anticuerpos Neutralizantes/análisis , Diabetes Mellitus Tipo 2/complicaciones , Hipersensibilidad a las Drogas/complicaciones , Drogas en Investigación/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/efectos adversos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Anticuerpos Neutralizantes/aislamiento & purificación , Reacciones Cruzadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inmunología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Erupciones por Medicamentos/complicaciones , Erupciones por Medicamentos/epidemiología , Erupciones por Medicamentos/fisiopatología , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/fisiopatología , Drogas en Investigación/administración & dosificación , Drogas en Investigación/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Hiperglucemia/inducido químicamente , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Incidencia , Inyecciones Subcutáneas , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Riesgo , Índice de Severidad de la Enfermedad , Extracción en Fase SólidaRESUMEN
Adolescence is a developmental period when many teenagers first drink alcohol and often engage in binge drinking. Early onset of alcohol is linked to increased risk of stress-related disorders in adulthood in humans, suggesting that alcohol may interfere with development of the stress regulatory system. We investigated the effect of voluntary alcohol exposure on corticotropin-releasing factor (CRF) peptide-producing cells in the central nucleus of the amygdala (CeA) in adolescent male and female rats. These cells are important for the autonomic and behavioral responses to stress, have been implicated in addiction, and change over adolescent development. Animals self-administered sweetened alcohol during early adolescence (postnatal days (PDs) 28-42) and brains were obtained on PD 43 for CRF peptide immunolabeling. Females had fewer CRF immunoreactive (-ir) cells in the CeA compared to males. In both males and females, alcohol self-administration reduced the number of CRF-ir cells in the CeA compared to control conditions in which rats self-administered equivalent levels of sweetened water that did not contain alcohol. Reduced peptide labeling was not observed in the bed nucleus of the stria terminalis, indicating regional specificity of these changes. Alterations within the CRF cell population of the amygdala may have important implications for susceptibility to alcohol and stress disorders during adolescence and later on in life.