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.
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).
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.
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