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.

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.

Network meta-analysis accurately predicted the outcome of a subsequent randomised trial comparing once weekly dulaglutide 1.5 mg and once daily liraglutide 1.8 mg.

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.

Initiating insulin therapy in elderly patients with Type 2 diabetes: efficacy and safety of lispro mix 25 vs. basal insulin combined with oral glucose-lowering agents.

AIMS: To compare starter insulins in the elderly subgroup of the DURABLE trial 24-week initiation phase. METHODS: In a post-hoc analysis of the > or = 65 years subgroup enrolled in the DURABLE trial, we compared the safety and efficacy of lispro mix 25 (LM25: lispro 25%/insulin lispro protamine suspension 75%), n = 258, vs. glargine, n = 222, added to oral glucose-lowering agents. RESULTS: Baseline glycated hemoglobin (HbA(1c)) was similar (LM25 8.7 +/- 1.2, glargine 8.8 +/- 1.1%, P = 0.612). At 24-weeks, LM25 patients had lower HbA(1c) (7.0 +/- 0.9 vs. 7.3 +/- 0.9%, P < 0.001), greater HbA(1c) reduction (-1.7 +/- 1.2 vs. -1.5 +/- 1.1%, P < 0.001), and more patients reaching HbA(1c) < 7.0% (55.6 vs. 41.0%, P = 0.005). LM25 patients were on more insulin (0.40 +/- 0.19 vs. 0.33 +/- 0.19 u/kg/day, P < 0.001) and experienced more weight gain (3.6 +/- 3.6 vs. 1.8 +/- 3.2 kg, P < 0.001). Additionally, LM25-treated patients reported a higher mean overall hypoglycaemia rate than glargine patients (40.8 +/- 47.6 vs. 31.1 +/- 48.5 episodes/patient/year, P = 0.037), while nocturnal hypoglycaemia rates were similar. Over 24 weeks, incidence of severe hypoglycaemia was higher for LM25 (4.3% vs. 0.9%, P = 0.018); however, by 24-week endpoint incidence was similar (0.8% vs. 0.0%P = 0.125). CONCLUSIONS: In this elderly subgroup post-hoc analysis, LM25 demonstrated a lower endpoint HbA(1c) and a higher % of patients reaching HbA(1c) target of < 7.0%, but with more weight gain and higher rates of hypoglycaemia compared to glargine.

Severe Myoclonic Epilepsy in Infancy - Adult Phenotype with Bradykinesia, Hypomimia, and Perseverative Behavior: Report of Five Cases.

Dravet syndrome or severe myoclonic epilepsy in infancy (SMEI) is an epileptic syndrome characterised by refractory epilepsy and intellectual disability, typically presenting with febrile and afebrile generalised and unilateral clonic/tonic-clonic seizures in the first year of life and other types of seizures appearing later in the course of the disease. Five adult patients with SMEI and SCN1A mutations are reported, in which motor and behavioural abnormalities were outstanding symptoms. Bradykinesia, responding with latency, slow speaking with a thin voice, midface hypomimia and perseveration were distinctive features in all cases. These symptoms may be fit to define the adult phenotype of SMEI beyond seizure/epilepsy criteria. The motor and behavioural symptoms are discussed in the context of a possibly underlying frontal lobe/mesofrontal and cerebellar dysfunction.