Divergent Hypoglycemic Effects of Hepatic-Directed Prandial Insulin: A 6-Month Phase 2b Study in Type 1 Diabetes

Diabetes Care. 2019 Nov;42(11):2154-2157. doi: 10.2337/dc19-0152. Epub 2019 Sep 24.


Objective: Hepatic-directed vesicle insulin (HDV) uses a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin's hepatic biodistribution. We assessed HDV-insulin lispro (HDV-L) versus insulin lispro (LIS) in type 1 diabetes (T1D).

Research design and methods: Insulin Liver Effect (ISLE-1) was a 26-week, phase 2b, multicenter, randomized, double-blind, noninferiority trial.

Results: Among 176 randomized participants (HDV-L n = 118, LIS n = 58), the difference in change from baseline A1C was 0.09% (95% CI -0.18% to 0.35%), confirming noninferiority (prespecified margin ≤0.4%). Overall, there were no statistically significant differences between treatments for hypoglycemia or insulin dosing. However, baseline A1C modified the treatment group effect (interaction P < 0.001) on clinically apparent hypoglycemia designated by treatment-blinded investigators as severe. Thus, at higher baseline A1C, there was less hypoglycemia and lower insulin dosing with similar A1C outcomes during HDV-L versus LIS, whereas greater risk of hypoglycemia despite similar A1C outcomes and insulin doses was observed with lower baseline A1C. Among poorly controlled participants (A1C ≥8.5%), incidence rates of severe hypoglycemia in the HDV-L and LIS arms were 69 and 97 events/100 person-years, respectively (P = 0.03), whereas with A1C <8.5%, respective rates were 191 and 21 events/100 person-years (P = 0.001). Similar A1C-dependent trends in hypoglycemia were seen with continuous glucose monitoring. Among poorly controlled participants, bolus insulin doses at end point were ∼25% lower with HDV-L (P = 0.02), despite similar A1C outcomes; in better-controlled participants, insulin doses and A1Cs were stable over time in both subgroups. No safety signals were identified.

Conclusions: Hepatic biodistribution of HDV-L appears to potentiate insulin effect in T1D, with divergent clinical outcomes in hypoglycemia dependent on baseline A1C.

Trial registration: ClinicalTrials.gov NCT02794155.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / drug effects
  • Blood Glucose Self-Monitoring
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glycated Hemoglobin / drug effects*
  • Humans
  • Hypoglycemia / drug therapy
  • Hypoglycemia / etiology
  • Hypoglycemic Agents / pharmacokinetics*
  • Insulin / pharmacokinetics*
  • Insulin Lispro / pharmacokinetics*
  • Liver / metabolism
  • Male
  • Meals
  • Middle Aged
  • Postprandial Period / drug effects
  • Tissue Distribution
  • Treatment Outcome


  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Insulin Lispro

Associated data

  • ClinicalTrials.gov/NCT02794155