Insulin degludec: Multihexamer formation as new protraction mechanism leads to a long and flat glucose lowering effect

Introduction: Insulin degludec (IDeg) is a new basal insulin with a flat and stable action profile. After s.c injection Ideg forms a depot of soluble multi-hexamers from which IDeg monomers are continuously released into circulation.

Methods: Transmission electron microscopy (TEM) was used to verify the formation of IDeg multihexamers. The pharmacodynamic consequences of IDeg multihexamer formation were investigated in people with type 1 diabetes. For TEM, samples of IDeg (5 zinc ions per insulin hexamer) were examined with a FEI Morgagni 268 electron microscope.

Results: Under conditions mimicking the sc interstitial fluid, elongated structures were seen with a uniform width consistent with the expected width of insulin hexamers. No such structures were visible under conditions corresponding to the pharmaceutical IDeg formulation, indicating that multihexamers only form after sc injection. Addition of EDTA to chelate zinc ions disrupted the multihexameric structures, showing that multihexamer formation is reversible, and suggesting that a gradual release of zinc ions from sc multihexamers leads to the release of IDeg monomers for absorption. The pharmacodynamic effect of IDeg was assessed in 42-h euglycemic glucose clamps (clamp blood glucose [BG] level: 100 mg/dl) conducted at steady state of once-daily dosing of IDeg (0.4, 0.6 or 0.8 U/kg). For all doses, the glucose-lowering effect of IDeg was > 42h. End of action (BG > 150 mg/dl) did not occur within the 42-h clamp period for any subjects dosed with 0.6 or 0.8 U/kg IDeg, and for only 3 of 21 subjects on 0.4 U/kg IDeg. Moreover, mean BG profiles measured over the 42-h clamp remained almost horizontal for the 0.6 and 0.8 U/kg dose groups showing that BG was controlled throughout.

Conclusion: Formation of soluble IDeg multihexamers at the sc injection contributes to the long glucose-lowering effect beyond 42h at clinically relevant doses in people with type 1 diabetes.