Insulin prandial injectable(Albireo Pharma, Inc.)

To conduct a substudy, using 24‐hour continuous glucose monitoring (CGM), of the AWARD‐4 trial, which was designed to compare insulin + glucagon‐like peptide‐1 receptor agonist treatment with an insulin‐only regimen.

The AWARD‐4 trial randomized 884 conventional insulin regimen‐treated patients to dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM substudy included 144 patients inserted with a Medtronic CGMS iPro CGM device to enable 3‐day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26 and 52. CGM measures included mean 24‐hour glucose, percentage time in target glucose ranges, hyper‐ and hypoglycaemia and glucose variability. The primary objective was treatment comparison for percentage time spent with CGM glucose values in the 3.9‐7.8 mmol/L range after 26 weeks.

At week 26, mean CGM values decreased in all treatment groups (change from baseline −2.8 ± 0.3, −2.4 ± 0.3 and −2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, respectively); between‐group differences were not statistically significant. Treatment groups were similar for percentage time in the 3.9‐7.8 mmol/L range. Percentage time in the 3.9‐10.0 mmol/L range was greater for dulaglutide 1.5 mg than for glargine (p < 0.05). Dulaglutide and glargine were associated with decreased glucose variability for all CGM variability indices. The overall within‐patient standard deviation (s.d.) was significantly reduced with dulaglutide 1.5 mg versus glargine (p < 0.05). At week 52, there were no significant differences among the groups with regard to measures of normoglycaemia or near‐normoglycaemia and for the overall within‐patient s.d. Treatment with glargine was associated with greater increases in percentage time spent with glucose values ≤3.9 mmol/L, with statistically significant differences between the groups at 52 weeks (p < 0.05).

In combination with prandial lispro, treatment with dulaglutide and glargine resulted in similar proportions of glucose values in the normoglycaemic range, but dulaglutide provided an improved balance between the proportion of values within the near‐normoglycaemia range and values within the hypoglycaemic range.

While the pharmacokinetic properties of the long-acting insulin analogues, insulin glargine and insulin detemir, clearly demonstrate clinical benefits over NPH insulin in terms of reduced frequency of overall and nocturnal hypoglycaemic events and lowered glycaemic variability, several new insulin analogues with even longer and smoother time-action profiles are being developed and explored. Among these, insulin degludec is the first to enter the market. The ultra-long action profile of this insulin analogue is mainly the result of a slow and stable release of insulin degludec monomers from soluble multihexamers that form after subcutaneous administration. In the last year, the results of the first phase II trials with insulin degludec have been published, where the efficacy and safety of this basal insulin analogue have been compared with insulin glargine in patients with type 1 (T1D) and type 2 (T2D) diabetes. With regard to short-acting insulins for mealtime insulin supplementation, there is also a search for new insulins with a more rapid onset of action, and hence improved postprandial glucose control. Linjeta (formerly named VIAject) is a human insulin formulation with faster insulin absorption and action than insulin lispro and regular human insulin. A new drug application to market Linjeta as a treatment for diabetes was submitted to the US Food and Drug Administration (FDA) by the manufacturer at the beginning of 2010. However, the FDA’s review cycle, which was announced late in 2010, concluded that the application could not be approved in its present form. The FDA’s complete response letter included comments related to clinical trials, statistical analysis and chemistry, manufacturing and controls. The FDA requested that the company should conduct two new phase III clinical trials using the commercial formulation, one in patients with T1D and the other in patients with T2D, to establish efficacy and safety with regard to hypoglycaemia and toleration. Co-administration of hyaluronidase together with insulin is another novel concept which has been proven to accelerate the absorption of both insulin lispro and regular human insulin in healthy subjects. In this review, we comment on two recent publications in which the pharmacokinetic and pharmacodynamic characteristics of Linjeta and co-formulations of prandial insulins with recombinant human hyaluronidase were investigated in patients with T1D. Lastly, a recent review on the ongoing discussion regarding insulin treatment and cancer risk is included.