LY 2605541 — A Preferential Hepato - Speci fi c Insulin

The first generation of basal insulin analogs, insulin glargine and detemir, are characterized by a more predictable day-to-day insulin absorption rate, a flatter time/action profile, and a longer duration than the older, intermediate-acting NPH insulin (1). The duration of insulin glargine is longer than insulin detemir (1). The second-generation basal insulin analog insulin degludec has an even longer half-life of about 25 h, a very flat profile of action with a duration exceeding 42 h, and a reduced risk of nocturnal hypoglycemia in both type 1 and type 2 diabetic patients compared with insulin glargine (2). Yet, there is still room for further refinements of the basal insulin analogues. Insulin treatment commonly results in weight gain; thus, an insulin analog associated with no weight gain or weight loss will be a great therapeutic advance. The peripheral administration of insulin does not replicate the twoto threefold higher portal versus systemic circulating insulin levels, causing an imbalance between hepatic and peripheral metabolic actions. Therefore, an insulin analog with hepatic specificity could be of interest. In this issue, Moore et al. (3) report on the effect of the novel basal insulin LY2605541 on hepatic and nonhepatic glucose uptake in their elegant dog model. During peripheral intravenous infusion of LY2605541, a switch from hepatic glucose output to uptake was reported, and nonhepatic glucose uptake increased less than in control experiments with human insulin, indicating that LY2605541 possesses preferential hepatic effects, thereby mimicking endogenously secreted insulin (3). The active component of LY2605541 is insulin lispro, a short-acting insulin analog, which is covalently coupled to a single 20-kilodalton polyethylene glycol (PEG) moiety via an urethane bound to lysine B28 (Fig. 1) (4,5). This results in a large hydrodynamic radius of the analog, delaying the absorption rate of insulin lispro by slowing diffusion rate and reducing renal filtration. The PEGylation of insulin lispro also prolongs its half-life by increasing stability against proteolysis. The increase in molecular size appears to alter the tissue distribution of this insulin (4,5). Hypothetically, the hepatic sinusoidal endothelium with its wide fenestration may allow greater transport of LY2605541 to the liver than to muscles and fat, ensuring a preferential hepatic action. Efficacy and safety of LY2605541 has been tested in two phase II studies (6,7). In a randomized 12-week open-label study in type 2 diabetic patients, once-daily basal insulin LY2605541 and insulin glargine were both administered in the morning (6). At 12 weeks, fasting blood glucose was similar in the two groups, as was HbA1c. Intraand interday blood glucose variability was reduced with LY2605541, which also induced a weight loss of 20.6 kg, compared with a weight gain of 0.3 kg in the insulin glargine group. The incidence of total and nocturnal hypoglycemia did not differ between the two groups, although LY2605541-treated patients had a 48% reduction in nocturnal hypoglycemia after adjusting for run-in period of hypoglycemia. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglycerides increased in the LY2605541 group and were higher than during insulin glargine treatment. The number of patients developing detectable antibodies against LY2605541 or insulin glargine did not differ between the groups (6). At week 12, mean insulin dose/kg was 1.5-fold greater with LY2605541 than with insulin glargine treatment (6). In another open-label crossover study, type 1 diabetic patients received once-daily LY2605541 or insulin glargine plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks (7). Mean daily glucose control evaluated from self-monitored blood glucose profiles (20.55 mmol/L), fasting blood glucose