Clinical Trial Data Reported for an Investigational Ultra-Rapid-Acting Insulin
The lag time from the time of injection to peak action is significantly longer for all current rapid-acting insulin analogs than for endogenous insulin. Faster-acting insulins are needed to more closely mimic physiological insulin secretion; the development of ultra-rapid-acting insulins is considered a key barrier to the development of a fully automated, closed-loop insulin delivery system (ie, artificial pancreas). This report summarizes an oral abstract presented on a monomeric, ultra-rapid-acting human insulin (Abstract 0036-OR) at the American Diabetes Association 70th Annual Scientific Sessions on June 25, 2010. In addition to better applicability for closed-loop insulin delivery, potential advantages of ultra-rapid-acting insulin include avoidance of hypoglycemia. According to the abstract presenter, Helena Rodbard, many patients experience hypoglycemia several hours after prandial injections of current rapid-acting insulins. This may be caused by intrinsic variability in insulin action, by longer than expected delay between insulin injection and meal consumption, or by fewer carbohydrates being consumed than were expected at the time the prandial insulin dose was injected. Ultra-rapid-acting insulins may be injected just before eating, reducing the uncertainties surrounding meal timing and meal carbohydrate content.
Data from a 6-month, open-label, randomized, multicenter, phase 3 clinical trial comprised of 471 patients with type 2 diabetes and comparing a monomeric human insulin with regular human insulin were presented. Regular human insulin is dimeric whereas the ultra-rapid-acting insulin is derived from regular human insulin by removing the zinc with EDTA and enveloping the resultant monomers with citric acid. Monomers work faster than dimers. In this study, patients were randomized 1:1 to monomeric human insulin or regular human insulin, administered as prandial doses used in combination with background therapies which could include glargine, metformin, or thiazolidinediones. The monomeric human insulin dose was started at 50% of the previous prandial insulin dose. Patients randomized to monomeric human insulin injected it immediately before each meal; it was unclear from both the oral presentation and the published version of Abstract 0036-OR the time at which patients randomized to regular human insulin administered their prandial injections.
After 6 months of treatment, the efficacy of monomeric human insulin was equivalent to regular human insulin, but the insulin dose, hypoglycemia rates, and weight gain were lower in the monomeric human insulin group. Change in A1C was –0.56% (baseline 8.18%) and –0.70% (baseline 8.19%) for monomeric human insulin and regular human insulin, respectively. Nonsevere hypoglycemic event rates were 0.33 events/month and 0.66 events/month for monomeric human insulin and regular human insulin, respectively (P < .02). Weight gain was 0.46 kg and 1.35 kg for monomeric human insulin and regular human insulin, respectively (P < .05).
Changes in postprandial glucose levels were not presented. Upon questioning, Dr Rodbard explained that monomeric human insulin was no more rapid than regular human insulin at the doses used in this trial, which were dictated by safety concerns, and that the 7-point glycemic profiles for the 2 insulins were equivalent. Dr Rodbard noted that the investigational insulin formulation was U-25 and had a pH of 4; it was associated with injection pain. The commercial formulation is expected to be formulated as U-100 with a pH of 7.