Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5).

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. 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. 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]. 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.

Skrivanek Z ，Gaydos BL ，Chien JY ，Geiger MJ ，Heathman MA ，Berry S ，Anderson JH ，Forst T ，Milicevic Z ，Berry D ... -  《-》

Patient-reported outcome results in patients with type 2 diabetes treated with once-weekly dulaglutide: data from the AWARD phase III clinical trial programme.

We evaluated patient-reported outcome (PRO) measures from the Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes (AWARD) clinical trial programme for dulaglutide (1.5 mg and 0.75 mg) in patients with type 2 diabetes (T2D). The Impact of Weight on Self-Perception (IW-SP), Impact of Weight on Ability to Perform Physical Activities of Daily Living (APPADL), Impact of Weight on Quality of Life-Lite, EQ-5D, Diabetes Treatment Satisfaction Questionnaire (DTSQ), Diabetes Symptom Checklist-Revised and Adult Low Blood Sugar Survey were administered and analysed for changes from baseline in one or more AWARD studies. Significant within-group changes from baseline to the primary time point were observed for several PRO measures across all studies. Compared with insulin glargine, significantly greater improvements in the IW-SP score were observed with dulaglutide 1.5 mg and with both dulaglutide doses in the APPADL score. Both dulaglutide doses resulted in significantly greater improvement in DTSQ scores (all subscales) compared with exenatide. Dulaglutide 1.5 mg also resulted in significantly greater improvement on the DTSQ hyperglycaemia subscale compared with metformin. Overall, these PRO results suggest that dulaglutide is beneficial in the treatment of T2D.

Yu M ，Van Brunt K ，Varnado OJ ，Boye KS ... -  《-》

Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9).

To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration. Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks. Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%). Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D.

Pozzilli P ，Norwood P ，Jódar E ，Davies MJ ，Ivanyi T ，Jiang H ，Woodward DB ，Milicevic Z ... -  《-》

Safety and efficacy of dulaglutide, a once weekly GLP-1 receptor agonist, for the management of type 2 diabetes.

Kuritzky L ，Umpierrez G ，Ekoé JM ，Mancillas-Adame L ，Landó LF ... -  《-》

A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on to glimepiride in type 2 diabetes (AWARD-8).

To evaluate the safety and efficacy of once-weekly dulaglutide 1.5 mg, a long-acting glucagon-like peptide-1 receptor agonist, compared with placebo in patients with type 2 diabetes (T2D) on glimepiride monotherapy. This phase III, randomized (4 : 1; dulaglutide:placebo), double-blind, placebo-controlled, 24-week study compared the safety and efficacy of once-weekly dulaglutide 1.5 mg with placebo in sulphonylurea-treated (≥half-maximal dose, stable ≥3 months) patients (N = 300) with T2D and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥7.5 and ≤9.5% (≥58 mmol/mol and ≤80 mmol/mol)]. Analysis was carried out according to intention-to-treat. At baseline, the mean participant age was 58 years; mean HbA1c was 8.4% (68 mmol/mol) and mean weight was 85.5 kg. Dulaglutide 1.5 mg was superior to placebo at 24 weeks for HbA1c reduction from baseline with a between-group HbA1c difference of -1.3% [95% confidence interval (CI) -1.6, -1.0] or -14 mmol/mol (95% CI -17, -11); p < 0.001. A greater proportion of participants in the dulaglutide group reached an HbA1c level of <7.0% (53 mmol/mol) compared with placebo (55.3% vs 18.9%; p < 0.001). Dulaglutide significantly decreased fasting serum glucose from baseline compared with placebo (between-group difference -1.86 mmol/l (95% CI -2.58, -1.14) or -33.54 mg/dl (95% CI -46.55, -20.53); p < 0.001. Weight was decreased significantly from baseline in the dulaglutide group (p < 0.001); the between-group difference was not significant. The most common treatment-emergent adverse events for dulaglutide 1.5 mg were gastrointestinal: nausea (10.5%), diarrhoea (8.4%) and eructation (5.9%). Total hypoglycaemia was higher with dulaglutide 1.5 mg vs placebo (2.37 and 0.07 events/participant/year, respectively; p = 0.025). No severe hypoglycaemia was reported. Once-weekly dulaglutide 1.5 mg had a favourable benefit/risk profile when added to glimepiride monotherapy.

Dungan KM ，Weitgasser R ，Perez Manghi F ，Pintilei E ，Fahrbach JL ，Jiang HH ，Shell J ，Robertson KE ... -  《-》