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

Abstract

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 METHODSInsulin Liver Effect (ISLE-1) was a 26-week, phase 2b, multicenter, randomized, double-blind, noninferiority trial. RESULTSAmong 176 randomized participants (HDV-L n 5 118, LIS n 5 58), the difference in change from baseline A1C was 0.09% (95% CI 20.18% 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 5 0.03), whereas with A1C <8.5%, respective rates were 191 and 21 events/100 person-years (P 5 0.001). Similar A1Cdependent 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 5 0.02), despite similar A1C outcomes; in bettercontrolled participants, insulin doses and A1Cs were stable over time in both subgroups. No safety signals were identified.

The future of insulin therapy

“…Another attempt to design a hepato-preferential insulin are Hepatic Directed Vesicles (HDV), phospholipid-based 20-50 nm bicell disc carriers, that are aimed at delivering a proportion (e.g., 1%) of the injected insulin to the liver targeting biotin receptors on hepatocytes. In a phase 2 study over 26 weeks patients with type 1 diabetes were randomised 2:1 to either HDV-bound insulin lispro (HDV-L) or conventional insulin lispro (LIS) [22]. HDV-L achieved HbA1c noninferiority to conventional insulin lispro (LIS) without significant differences in insulin doses or times in hypoglycaemia (<24 mg/dl).…”

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

“…Hepatic-directed vesicle (HDV) insulin is another insulin delivery system that contains biotin-phosphatidylethanolamine as a hepatocyte-targeting molecule in phospholipid bilayer vesicles [ 81 ]. In a phase 2b study of T1DM, HDV insulin lispro showed noninferior HbA1c lowering and no significant differences in hypoglycemia or insulin dosing compared with insulin lispro [ 82 ]. Further delineation of its efficacy and safety is awaited.…”

The promising future of insulin therapy in diabetes mellitus

“…However, this drug was associated with liver enzyme and lipid abnormalities, resulting in its discontinuation (29). Other emerging insulins are currently being engineered to resemble PegLispro without its side effects and include coupling insulin lispro with vesicles that confer hepatoselectivity (31,45).…”