Improved Postprandial Glycemic Control in Patients with Type 2 Diabetes from Subcutaneous Injection of Insulin Lispro with Hyaluronidase

Background: Coinjection of hyaluronidase has been shown to accelerate insulin absorption in healthy volunteers and patients with type 1 diabetes mellitus. This study was undertaken to compare the postprandial glycemic response of patients with type 2 diabetes mellitus (T2DM) administered insulin lispro with and without recombinant human hyaluronidase (rHuPH20) and regular human insulin (RHI) with rHuPH20. Methods: This double-blind three-way crossover study compared the insulin pharmacokinetics and glucodynamic response to a standardized liquid meal (80 g of carbohydrate) in 21 patients with T2DM who received subcutaneous injections of individually optimized doses of lispro +/- rHuPH20 and RHI + rHuPH20. The optimum dose (targeting postprandial glucose [PPG] of 70-140 mg/dL) of each preparation was selected by the investigator following a fixed-dose escalation procedure in three dose-finding meals. Results: Co-injection of lispro + rHuPH20 accelerated pharmacokinetics relative to lispro alone (time to peak insulin concentration, 43 vs. 74 min; P = 0.0045) with increased exposure in the first hour (184% of control; P < 0.0001) and reduced exposure after 2 h (67% of control; P = 0.0001). These accelerated pharmacokinetics improved both total hyperglycemic excursions (area under the curve for 0-4 h > 140mg/dL, 56% of control; P = 0.048) and hypoglycemic excursions (area under the curve for 0-8 h < 70 mg/dL, 34% of control; P = 0.033), allowing over three times as many patients to reach the American Diabetes Association's target of peak PPG < 180 mg/dL without requiring glucose treatment for hypoglycemia. The mean optimum dose of lispro was reduced 8% from 0.275 U/kg without rHuPH20 to 0.254 U/kg with rHuPH20 (P = 0.04). RHI + rHuPH20 had responses and optimum doses comparable to insulin lispro alone. All insulin preparations were well tolerated. Conclusions: Lispro + rHuPH20 provided superior control of glycemic excursion compared with lispro alone, with lower insulin requirements and reduced hypoglycemic excursions.