Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis.

INTRODUCTION: To evaluate the efficacy and safety of dulaglutide 0.75 and 1.5 mg in patients with type 2 diabetes mellitus (T2DM) by baseline glycated hemoglobin (HbA1c) < 8.5% or ≥ 8.5% after 26 weeks of treatment. METHODS: Assessment of the Weekly AdministRation of dulaglutide in Diabetes (AWARD) China 1 (CHN1) study (NCT01644500, n = 556) included patients on dulaglutide vs. glimepiride who were treatment naïve or on monotherapy but discontinued therapy. AWARD-CHN2 (NCT01648582, n = 591) patients were on dulaglutide vs. insulin glargine and continued on metformin and/or sulfonylurea. Mean daily dose of glimepiride and insulin glargine was 2.51 mg and 21.0 IU, respectively. Post hoc analyses were conducted based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the Chinese population. Change from baseline in HbA1c and body weight was analyzed by individual study. RESULTS: In the two studies, 70.1% of patients in AWARD-CHN1 and 59.7% in AWARD-CHN2 had baseline HbA1c < 8.5% (mean HbA1c 7.4% and 7.6%, respectively) and 29.9% in AWARD-CHN1 and 40.3% in AWARD-CHN2 had baseline HbA1c ≥ 8.5% (mean HbA1c 9.2% and 9.4%, respectively). In AWARD-CHN1, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.1% and - 2.2%; dulaglutide 0.75 mg: - 0.9% and - 2.0%; glimepiride: - 0.7% and - 1.4%. In AWARD-CHN2, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.2% and - 2.3%; dulaglutide 0.75 mg: - 1.0% and - 1.7%; and insulin glargine: - 0.6% and - 1.7%. Irrespective of baseline HbA1c, body weight decreased with both dulaglutide doses and increased with either glimepiride or insulin glargine at 26 weeks. Dulaglutide demonstrated low incidence of hypoglycemia in both doses in the two trials. Hypoglycemia incidence was generally lower in patients with baseline HbA1c ≥ 8.5%. CONCLUSIONS: Dulaglutide demonstrated significantly greater HbA1c reduction with weight loss and lower risk of hypoglycemia compared with active comparators in Chinese patients with T2DM irrespective of baseline HbA1c, with much greater HbA1c reductions in patients with a higher baseline HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01644500 and NCT01648582.

Roxithromycin suppresses airway remodeling and modulates the expression of caveolin-1 and phospho-p42/p44MAPK in asthmatic rats.

Roxithromycin (RXM) expresses anti-asthmatic effects that are separate from its antibiotic activity, but its effects on airway remodeling are still unknown. Here, we evaluated the effects of RXM on airway remodeling and the expression of caveolin-1 and phospho-p42/p44mitogen-activated protein kinase (phospho-p42/p44MAPK) in chronic asthmatic rats. The chronic asthma was induced by ovalbumin/Al(OH)3 sensitization and ovalbumin challenge, RXM (30mg/kg) or dexamethasone (0.5mg/kg) was given before airway challenge initiation. We measured the thickness of bronchial wall and bronchial smooth muscle cell layer to indicate airway remodeling, and caveolin-1 and phospho-p42/p44MAPK expression in lung tissue and airway smooth muscle were detected by immunohistochemistry and western blot analysis, respectively. The results demonstrated that RXM treatment decreased the thickness of bronchial wall and bronchial smooth muscle cell layer, and also downregulated the phospho-p42/p44MAPK expression and upregulated the caveolin-1 expression. The above effects of RXM were similar to dexamethasone. Our results suggested that pretreatment with RXM could suppress airway remodeling and regulate the expression of caveolin-1 and phospho-p42/p44MAPK in chronic asthmatic rats.

[Insulin ultradian pulse model of individuals with overweight and impaired glucose tolerance].

OBJECTIVE: To study the characteristics of insulin ultradian pulses of individuals with normal glucose tolerance, overweight, and impaired glucose tolerance (IGT). METHODS: Blood samples were taken every 15 minutes from 10 individuals with normal glucose tolerance, 6 individuals with overweight and 3 individuals with IGT for 24 hours. Blood glucose, insulin, and C-peptide of every time point were measured. Standard diet was used in the study. The 24 h-ISR profile was submitted to time series analysis. RESULTS: (1) As given standard diet, 2 to 4 pulses occurred after each meal, 3 to 4 pulses occurred during the night, and 12 to 15 pulses occurred in the whole 24-hour period. The first insulin pulse always occurs 30 to 60 minutes after meal. The maximum amplitude of pulse occurred 45 to 90 minutes after meal. These characteristics were not significantly different among the 3 groups. (2) The average amplitude of 24-hour insulin secretion rate (ISR) of the normal group was 357 pmol/min +/- 11 pmol/min, significantly lower than those of the overweight and IGT groups (820 pmol/min +/- 37 pmol/min and 666 pmol/min +/- 53 pmol/min respectively, both P < 0.05). (3) The average periodicity of insulin ultradian pulse were 75 min and 75 - 90 min in the control group and overweight group respectively. The periodicity of insulin ultradian pulse in the IGT group was undefined. (4) The cross-correlation function were 0.72 +/- 0.11, 0.80 +/- 0.11 and 0.51 +/- 0.11 respectively in the normal, overweight, and IGT groups. CONCLUSION: (1) As given standard diet, the occurring numbers and time of insulin ultradian oscillations are not statistically significantly different among the normal, overweight, and IGT groups. (2) The insulin secretion amplitude is increased in the overweight and IGT groups. (3) The rhythm and concomitance coefficient of the ISR and glucose are low in the individuals with IGT.