Abstract
Background and Aims
SC insulin is non-physiologic since the pancreas normally releases insulin directly to the liver. Using a liver-targeting lipid moiety (Hepatic Directed Vesicles: HDV), Diasome technology enables subcutaneous insulin to be delivered to the liver, restoring more physiologic hepatic glucose balance. We assessed safety and efficacy of HDV-Lispro (HDV-L), compared to lispro alone (LIS), in type 1 diabetes subjects (T1DM).
Methods
The ISLE-1 (InSulin Liver Effect-1) a 26-week randomized (2:1 HDV-L:LIS) double-blind study, enrolled 176 generally healthy T1DM with baseline A1C 7.0-10.5%. Recent severe hypoglycemia and impaired hypoglycemia awareness were exclusionary. Primary study endpoint was A1C noninferiority, with multiple secondary endpoints.
Results
141 subjects (HDV-L=98;LIS=58) completed the study. Overall, mean change in A1C from baseline to endpoint was -0.09% for HDV-L and -0.16% for LIS (CI -0.18 to 0.35, confirming noninferiority of HDV-L). Overall, no statistically significant differences in measures of hypoglycemia or insulin dosing were observed. Prespecified subgroups demonstrated an inverse relationship between baseline A1C and measures of hypoglycemia, confirmed by interaction analysis (p<0.001). High baseline A1C (>8.5%) had less hypoglycemia [e.g. 73% reduced time <54 mg/dL by continuous glucose monitoring (CGM)] while using 25% less prandial insulin despite similar A1C response, and low A1C (<8.5%) had 3-fold increased hypoglycemia by CGM (p=0.16) with similar A1C and insulin dosing. Importantly, high A1C HDV-L subjects who achieved endpoint A1C<8.5% also had lower hypoglycemia and insulin dosing at endpoint.
Conclusions
HDV-L is noninferior to LIS, and provides insulin dosing and hypoglycemia benefits to poorly controlled T1DM.
