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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Once-weekly dulaglutide 1.5 mg had a favourable benefit/risk profile when added to glimepiride monotherapy.

Achieving the composite endpoint of glycated haemoglobin <7.0%, no weight gain and no hypoglycaemia in the once-weekly dulaglutide AWARD programme.

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.

Effect of the approach to insulin therapy on glycaemic fluctuations and autonomic tone in hospitalized patients with diabetes.

AIMS: Glycaemic variability (GV) is associated with mortality in acutely ill patients, but the mechanism is unknown. The objective of this study is to determine whether common approaches to insulin therapy have distinct effects on GV and autonomic tone. METHODS: Hospitalized patients with diabetes were randomized to short-term intravenous (IV) or physiologic subcutaneous (SQ) insulin. Heart rate variability (HRV) and cardiac impedance (pre-ejection period, PEP) were used to estimate parasympathetic and sympathetic tone, respectively. GV was measured using a continuous glucose monitor. RESULTS: Mean glucose tended to be lower initially in the SQ group (N = 16) compared with the IV group (N = 17) on day 1 (10.5 vs. 8.6 mmol/l, p = 0.05), but became non-significant during the transition off of the infusion. There was no difference in glycaemic lability index (GLI), continuous overlapping net glycaemic action (CONGA) or coefficient of variation (CV) on day 1, but by day 2, these measures were higher in the IV group (p < 0.05 for all). PEP was higher in the SQ group during (110 vs. 123 ms, p = 0.02) and after the intervention (104 vs. 126 ms, p = 0.004). Hypoglycaemia was similar in both groups. There were only small differences in HRV. Post-treatment PEP was inversely correlated with log GLI (r = -0.41, p = 0.03) but not other measures. CONCLUSIONS: Short-term IV insulin is associated with an increase in multiple GV measures compared with optimal SQ insulin. However, GLI was the only predictor of PEP. Further research is needed to determine if interventions that minimize GV improve outcomes in the hospital.