Hepatic-directed vesicle insulin, a novel liver-targeted rapid-acting insulin formulation for type 1 diabetes (T1D), is noninferior to insulin lispro for improvement of glycated hemoglobin (HbA1c) and is associated with a lower hypoglycemia risk in some patients, according to study results published in Diabetes Care.

Hepatic-directed vesicle insulin is an insulin delivery system that uses biotin-phosphatidylethanolamine in a phospholipid matrix, targets insulin to the liver, and was shown to have a flat dose-response for hepatic glucose balance and oral glucose tolerance results in preclinical studies. The goal of this noninferiority study was to compare hepatic-directed vesicle insulin lispro with insulin lispro in combination with basal insulin.

The Insulin Liver Effect-1 study was a 26-week phase 2b randomized double-blind trial that included adult patients with T1D and HbA1c between 7.0% and 10.5% who were followed at 21 North American sites and treated with multiple daily injections of insulin.

Continue Reading

Of 176 patients who were randomly assigned to treatment, 141 completed the study: 98 received hepatic-directed vesicle insulin lispro (mean age, 46.7±14.4 years; mean baseline HbA1c, 8.12%±0.79%) and 43 received insulin lispro (mean age, 44.1±15.7 years; mean baseline HbA1c, 8.22%±0.90%).

Mean change in HbA1c from baseline to week 26 was -0.09% with hepatic-directed vesicle insulin lispro and -0.16% with insulin lispro (estimated treatment difference, 0.09%; 95% CI, -0.18% to 0.35%) for the modified intention-to-treat population, confirming noninferiority of hepatic-directed vesicle insulin lispro (prespecified margin for treatment difference, ≤0.4%).

Although overall there were no statistically significant differences observed between groups in measures of hypoglycemia or insulin dosing, in a prespecified subgroup analysis, baseline HbA1c (<8.5% vs ≥8.5%) was shown to modify treatment group effect on the incidence of severe hypoglycemia (P <.001).

Related Articles

Although patients with poorly controlled T1D (HbA1c ≥8.5%) had a similar reduction in HbA1c (approximately 0.5% at week 26) in both groups, those treated with hepatic-directed vesicle insulin lispro did not experience significant changes in insulin dose over time and used approximately 25% less bolus insulin vs those treated with insulin lispro. The risk for severe hypoglycemia was lower with hepatic-directed vesicle insulin lispro compared with insulin lispro (69 vs 97 events/100 person-years, respectively; P =.03).

Among patients with baseline HbA1c <8.5%, there was little change in HbA1c over time and no difference in insulin dosage for either treatment. Incidence of severe hypoglycemia was higher with hepatic-directed vesicle insulin lispro compared with insulin lispro (191 vs 21 events/100 person-years, respectively; P =.001).

The researchers acknowledged several study limitations, including no standardized definition of severe hypoglycemia, a relatively small control group, limited continuous glucose monitoring data, and disparity in baseline insulin doses.

Overall, their results suppose hepatic-directed vesicle insulin lispro “as being noninferior to [insulin lispro] for A1C outcomes and suggest that [hepatic-directed vesicle insulin lispro] may be associated with less hypoglycemia in poorly controlled patients. Additional studies are needed to optimize insulin dosing with bolus [hepatic-directed vesicle insulin lispro], especially for A1C < 8.5%,” concluded the researchers.

Disclosure: This clinical trial was supported by Diasome Pharmaceuticals, Inc. Please see the original reference for a full list of authors’ disclosures.

Follow @EndoAdvisor


Klonoff D, Bode B, Cohen N, Penn M, Geho WB, Muchmore DB. Divergent hypoglycemic effects of hepatic-directed prandial insulin: a six-month phase 2b study in type 1 diabetes [published online September 24, 2019]. Diabetes Care. doi:10.2337/dc19-0152