RESUMEN
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
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are an established treatment for people with type 2 diabetes (T2D). We aimed to indirectly compare two GLP-1 receptor agonists, once weekly dulaglutide 1.5 mg and once daily liraglutide 1.8 mg, as a part of clinical trial planning. METHODS: Studies for inclusion in the network meta-analysis (NMA) included all available dulaglutide and liraglutide data as of November 2011 as well as results from the exenatide once weekly registration programme. Change from baseline in haemoglobin A1c (A1c) was the primary endpoint, and a 26-week treatment effect was estimated. RESULTS: Data for 7135 people with T2D from 15 randomised controlled trials (RCTs) followed for 12-52 weeks were included in the quantitative analysis. Observed results from the NMA predicted an A1c change from baseline of -15.1 mmol/mol (-1.38%) in the dulaglutide 1.5 mg group and -14.7 mmol/mol (-1.34%) in the liraglutide 1.8 mg group, with a predicted treatment difference (dulaglutide-liraglutide) of -0.4 mmol/mol (-0.04%) [95% credible interval: -2.4 to 1.5 mmol/mol (-0.22% to 0.14%)]. CONCLUSIONS: The subsequent RCT primary result of a -0.7 mmol/mol (-0.06%) treatment difference (dulaglutide-liraglutide) in A1c demonstrated that once weekly dulaglutide 1.5 mg and once daily liraglutide 1.8 mg resulted in similar glycaemic control, which was consistent with the NMA-predicted treatment difference. NMA is a useful tool and should be considered during clinical trial planning.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Liraglutida/administración & dosificación , Péptidos/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Ponzoñas/administración & dosificación , Esquema de Medicación , Exenatida , Péptidos Similares al Glucagón/administración & dosificación , Humanos , Metaanálisis en Red , Resultado del TratamientoRESUMEN
AIM: To compare the effectiveness of dulaglutide 1.5 and 0.75 mg with active comparators and placebo with regard to a composite endpoint of glycated haemoglobin (HbA1c), weight and hypoglycaemia, using post hoc analyses. METHODS: A logistic regression analysis was performed on the intention-to-treat population, using data from the last observation carried forward, and the composite endpoint of HbA1c <7.0% (53 mmol/mol), no weight gain (≤0 kg) and no hypoglycaemia (glucose <3.0 mmol/l or severe hypoglycaemia) after 26 weeks for each trial in the AWARD programme separately. RESULTS: At 26 weeks, within each study, 37-58% of patients on dulaglutide 1.5 mg, 27-49% of patients on dulaglutide 0.75 mg, and 9-61% of patients on active comparators achieved the composite endpoint. Significantly more patients reached the composite endpoint with dulaglutide 1.5 mg than with metformin, sitagliptin, exenatide twice daily or insulin glargine: odds ratio (OR) 1.5 [95% confidence interval (CI) 1.0, 2.2; p < 0.05], OR 4.5 (95% CI 3.0, 6.6; p < 0.001), OR 2.6 (95% CI 1.8, 3.7; p < 0.001) and OR 7.4 (95% CI 4.4, 12.6; p < 0.001), respectively, with no difference between dulaglutide 1.5 mg and liraglutide 1.8 mg. In addition, significantly more patients reached the composite endpoint with dulaglutide 0.75 mg than with sitagliptin or insulin glargine: OR 3.3 (95% CI 2.2, 4.8; p < 0.001) and OR 4.5 (95% CI 2.7, 7.8; p < 0.001), respectively. CONCLUSIONS: Dulaglutide is an effective treatment option, resulting in a similar or greater proportion of patients reaching the HbA1c target of <7.0% (53 mmol/mol), without weight gain or hypoglycaemia compared with active comparators.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Aumento de Peso/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Esquema de Medicación , Exenatida , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Liraglutida/administración & dosificación , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Péptidos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Fosfato de Sitagliptina/administración & dosificación , Resultado del Tratamiento , Ponzoñas/administración & dosificaciónRESUMEN
AIMS: To compare the once-weekly glucagon-like peptide-1 (GLP-1) receptor dulaglutide with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin after 104 weeks of treatment. METHODS: This AWARD-5 study was a multicentre, double-blind trial that randomized participants to dulaglutide (1.5 or 0.75 mg) or sitagliptin 100 mg for 104 weeks or placebo (reported separately) for 26 weeks. Change in glycated haemoglobin (HbA1c) concentration from baseline was the primary efficacy measure. A total of 1098 participants with HbA1c concentrations ≥7.0% (≥53.0 mmol/mol) and ≤9.5% (≤80.3 mmol/mol) were randomized, and 657 (59.8%) completed the study. We report results for dulaglutide and sitagliptin at the final endpoint. RESULTS: Changes in HbA1c at 104 weeks were (least squares mean ± standard error) -0.99 ± 0.06% (-10.82 ± 0.66 mmol/mol), -0.71 ± 0.07% (-7.76 ± 0.77 mmol/mol) and -0.32 ± 0.06% (-3.50 ± 0.66 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg and sitagliptin, respectively (p < 0.001, both dulaglutide doses vs sitagliptin). Weight loss was greater with dulaglutide 1.5 mg (p < 0.001) and similar with 0.75 mg versus sitagliptin (2.88 ± 0.25, 2.39 ± 0.26 and 1.75 ± 0.25 kg, respectively). Gastrointestinal adverse events were more common with dulaglutide 1.5 and 0.75 mg versus sitagliptin (nausea 17 and 15% vs 7%, diarrhoea 16 and 12% vs 6%, vomiting 14 and 8% vs 4% respectively). Pancreatic, thyroid, cardiovascular and hypersensitivity safety were similar across groups. CONCLUSIONS: Dulaglutide doses provided superior glycaemic control and dulaglutide 1.5 mg resulted in greater weight reduction versus sitagliptin at 104 weeks, with acceptable safety.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Metformina/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada/métodos , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Hemoglobina Glucada/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS: Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.
Asunto(s)
Fármacos Antiobesidad/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Metformina/uso terapéutico , Receptores de Glucagón/agonistas , Proteínas Recombinantes de Fusión/administración & dosificación , Adolescente , Adulto , Anciano , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/uso terapéutico , Terapia Combinada/efectos adversos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Dieta Reductora , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/efectos adversos , Ejercicio Físico , Femenino , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Sobrepeso/complicaciones , Sobrepeso/tratamiento farmacológico , Sobrepeso/terapia , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. METHODS: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. RESULTS: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. CONCLUSIONS: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Hipoglucemiantes/farmacología , Lípidos/sangre , Lovastatina/farmacocinética , Péptidos/farmacología , Ponzoñas/farmacología , Adolescente , Adulto , Anciano , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Interacciones Farmacológicas , Exenatida , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Lovastatina/sangre , Lovastatina/uso terapéutico , Masculino , Persona de Mediana Edad , Péptidos/uso terapéutico , Ponzoñas/uso terapéuticoRESUMEN
AIMS: Exenatide is an incretin mimetic whose effect on glycaemic control in patients with Type 2 diabetes is currently under investigation. This study assessed the effect of injection time relative to a standardized meal on postprandial pharmacodynamics of exenatide in patients with Type 2 diabetes. METHODS: Eighteen patients participated in this single-centre, open-label, placebo-controlled, randomized, six-way crossover study. Patients received subcutaneous injections of either placebo (-15 min) or 10 microg of exenatide at -60, -15, 0, +30 or +60 min relative to a standardized breakfast meal on six consecutive days. Serial blood samples were assayed for plasma glucose and insulin concentrations. RESULTS: For all exenatide treatments, incremental postprandial glucose area under the postprandial plasma glucose curve from zero to 6 h (AUC0-6 h) was significantly reduced compared with placebo. When exenatide was administered before (-60, -15 min) or with the meal (0 min), peak postprandial glucose concentrations were significantly decreased (P < 0.0001 for all treatments) compared with placebo. Post-meal exenatide administration (+30, P < 0.05; +60 min, P = 0.21) resulted in smaller peak glucose reductions and in some patients transient low plasma glucose concentrations were reported. Peak plasma insulin concentrations in the pre-meal treatments were significantly lower than placebo (P < 0.05 for all treatments), while post-meal dosing groups exhibited a trend towards higher insulin peaks compared with placebo. The most common adverse events related to exenatide were headache, nausea, dyspepsia and vomiting, and were generally of mild-to-moderate intensity. CONCLUSIONS: In this study, all exenatide treatments demonstrated reductions in postprandial plasma glucose excursions compared with placebo. Pre-meal and with meal administration of exenatide produced greater reduction of postprandial glucose excursions compared with post-meal administration. These data support flexible dosing of exenatide at any time within 60 min before a meal.