RESUMO
AIMS: To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. METHODS: Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). RESULTS: Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. CONCLUSIONS: Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Peptídeos/administração & dosagem , Pirazinas/administração & dosagem , Triazóis/administração & dosagem , Peçonhas/administração & dosagem , Adolescente , Adulto , Idoso , Argentina/epidemiologia , Austrália/epidemiologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Método Duplo-Cego , Esquema de Medicação , Exenatida , Feminino , Alemanha/epidemiologia , Hemoglobinas Glicadas/metabolismo , Grécia/epidemiologia , Humanos , Hipoglicemia/sangue , Hipoglicemia/epidemiologia , Hipoglicemiantes/farmacologia , Índia/epidemiologia , Masculino , Metformina/farmacologia , México/epidemiologia , Pessoa de Meia-Idade , Peptídeos/farmacologia , Pirazinas/farmacologia , República da Coreia/epidemiologia , Fosfato de Sitagliptina , Resultado do Tratamento , Triazóis/farmacologia , Peçonhas/farmacologiaRESUMO
It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing's disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing's disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing's disease (8 female, 2 male; age: 36.7 +/- 4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2 microg/kg iv) and DDAVP (10 micro g i.v.) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean +/- SE; basal: 15.5 +/- 1.7 vs peak: 45.1 +/- 9.3) and cortisol values (nmol/l, basal: 583.0 +/- 90.8 vs peak: 1013.4 +/- 194.6). ACTH AUC (pmol/l min(-1)) and cortisol AUC (nmol/l min(-1)) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0 +/- 1.4 vs peak: 50.5 +/- 16.2) and cortisol levels (basal: 572.5 +/- 112.7 vs peak: 860.5 +/- 102.8. AUC values for ACTH and cortisol were 1627.6 +/- 639.8 and 18364.7 +/- 5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1 +/- 9.3 vs 50.5 +/- 16.2; AUC: 1235.4 +/- 424.8 vs 1627.6 +/- 639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r = 0.87, p = 0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing's disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.