Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized,crossover study

OBJECTIVE

To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL.

RESULTS

LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02).

CONCLUSIONS

In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.The quest to prolong the action of insulin, which led to modern basal insulins, began in the 1930s with development of protamine zinc insulin (1,2). Basal insulins, such as protamine zinc, lente, isophane (NPH insulin), and ultralente insulins, were originally developed as suspensions to prolong action by delaying absorption (3,4). More recently, insulins glargine (GL) and detemir were developed to prolong subcutaneous absorption by altering amino acid structure (GL) or adding fatty acylated side chains (detemir) (4,5). Insulin degludec, a basal insulin in development, has the goal to achieve an effect longer than 24 h by prolonging subcutaneous absorption (6). Longer-acting insulins may be expected to reduce the need for twice-daily injections, variability, and the risk of hypoglycemia, as well as to provide minimal peak activity. Despite these refinements, current basal insulins cannot restore physiologic distribution of the twofold portal to systemic insulinemia because of subcutaneous systemic absorption, which results in similar portal and systemic levels. Thus, reduced hepatic insulin action must be balanced with excess peripheral insulin action to maintain glucose homeostasis.LY2605541 is a novel, long-acting basal insulin consisting of insulin lispro covalently modified with a 20-kDa polyethylene glycol moiety. It is a solution-based basal insulin with a time-action profile that is believed to be modulated indirectly through slowed depot absorption and reduced clearance due to increased molecular size. LY2605541 has a duration of action of more than 36 h with low variability, acting considerably longer than insulin glargine (7).This exploratory Phase 2 clinical trial was designed to determine if LY2605541 was noninferior to insulin GL for reduction of daily mean blood glucose (BG) in patients with type 1 diabetes on a basal-bolus regimen and to compare safety and efficacy of LY2605541 and insulin GL.